Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass.

Nat Med. 2012 Feb 5;

Authors: Guan M, Yao W, Liu R, Lam KS, Nolta J, Jia J, Panganiban B, Meng L, Zhou P, Shahnazari M, Ritchie RO, Lane NE

Abstract

Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.

PMID: 22306732 [PubMed - as supplied by publisher]

Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.

Nat Med. 2012 Feb 5;

Authors: Sugimoto H, Lebleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W, Bey P, Rusckowski M, Tampe B, Tampe D, Kanasaki K, Zeisberg M, Kalluri R

Abstract

Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.

PMID: 22306733 [PubMed - as supplied by publisher]

Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling.

Nat Immunol. 2012 Feb 5;

Authors: Seiler MP, Mathew R, Liszewski MK, Spooner C, Barr K, Meng F, Singh H, Bendelac A

Abstract

Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4(+)CD8(+) thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to ‘instruct’ a thymic lineage.

PMID: 22306690 [PubMed - as supplied by publisher]

The composition and signaling of the IL-35 receptor are unconventional.

Nat Immunol. 2012 Feb 5;

Authors: Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DA

Abstract

Interleukin 35 (IL-35) belongs to the IL-12 family of heterodimeric cytokines but has a distinct functional profile. IL-35 suppresses T cell proliferation and converts naive T cells into IL-35-producing induced regulatory T cells (iTr35 cells). Here we found that IL-35 signaled through a unique heterodimer of receptor chains IL-12Rβ2 and gp130 or homodimers of each chain. Conventional T cells were sensitive to IL-35-mediated suppression in the absence of one receptor chain but not both receptor chains, whereas signaling through both chains was required for IL-35 expression and conversion into iTr35 cells. Signaling through the IL-35 receptor required the transcription factors STAT1 and STAT4, which formed a unique heterodimer that bound to distinct sites in the promoters of the genes encoding the IL-12 subunits p35 and Ebi3. This unconventional mode of signaling, distinct from that of other members of the IL-12 family, may broaden the spectrum and specificity of IL-35-mediated suppression.

PMID: 22306691 [PubMed - as supplied by publisher]

A CD74-dependent MHC class I endolysosomal cross-presentation pathway.

Nat Immunol. 2012 Feb 5;

Authors: Basha G, Omilusik K, Chavez-Steenbock A, Reinicke AT, Lack N, Choi KB, Jefferies WA

Abstract

Immune responses are initiated and primed by dendritic cells (DCs) that cross-present exogenous antigen. The chaperone CD74 (invariant chain) is thought to promote DC priming exclusively in the context of major histocompatibility complex (MHC) class II. However, we demonstrate here a CD74-dependent MHC class I cross-presentation pathway in DCs that had a major role in the generation of MHC class I-restricted, cytolytic T lymphocyte (CTL) responses to viral protein- and cell-associated antigens. CD74 associated with MHC class I in the endoplasmic reticulum of DCs and mediated the trafficking of MHC class I to endolysosomal compartments for loading with exogenous peptides. We conclude that CD74 has a previously undiscovered physiological function in endolysosomal DC cross-presentation for priming MHC class I-mediated CTL responses.

PMID: 22306692 [PubMed - as supplied by publisher]

Treatment and outcomes of acute intracranial vertebrobasilar artery occlusion: one institution’s experience.

J Neurosurg. 2012 Feb 3;

Authors: Webb S, Yashar P, Kan P, Siddiqui AH, Hopkins LN, Levy EI

Abstract

Object The treatment of acute intracranial vertebrobasilar artery occlusion (VBO) has been described but often with poor results. The authors of this study set out to evaluate their institution’s outcomes following multimodal treatment of VBO. Methods They retrospectively reviewed their endovascular database for all patients treated for acute intracranial VBO between December 2004 and June 2010. Twenty-four patients were identified. Two patients were excluded from evaluation-one because of incomplete medical records and one because the etiology was basilar stenosis and not stroke. Occlusion location, hypercoagulable causes, time to endovascular treatment, time to revascularization, comorbidities, devices used, procedural anticoagulation, and outcomes were analyzed. Results Among the 22 eligible study patients, the mean National Institutes of Health Stroke Scale (NIHSS) score at presentation was 15.3. The mean time from presentation to initiation of the endovascular procedure was 4.77 hours. The mean time for recanalization from the start of angiography was 1.63 hours. In 16 patients (73%), revascularization was successful (Thrombolysis in Myocardial Infarction [TIMI] score of 2 or 3). Thirteen (59%) of the 22 patients were discharged to home or a rehabilitation facility. One patient was transferred to a chronic care facility. The overall survival rate was 64%. The average NIHSS score for the 14 surviving patients at discharge was 3.9. At the follow-up (average 14.5 months, range 1-58 months), 10 patients (71%) had achieved good outcomes (modified Rankin Scale [mRS] score ≤ 2) and 4 (29%) had poor outcomes (mRS Score 3-6). Conclusions Published case series have historically shown poor outcomes and high mortality rates in association with the treatment of acute VBO, prompting surgeons to be less aggressive in the treatment of this disease than they might be otherwise. Data in this series show that the revascularization of posterior circulation occlusions is feasible and that good outcomes and lower mortality rates with newer endovascular technologies are possible, and thus more prompt and aggressive treatment of this disease may be warranted.

PMID: 22304447 [PubMed - as supplied by publisher]

Crocodile tears syndrome after vestibular schwannoma surgery.

J Neurosurg. 2012 Feb 3;

Authors: Nakamizo A, Yoshimoto K, Amano T, Mizoguchi M, Sasaki T

Abstract

Object Crocodile tears syndrome (CTS) is a lacrimal hypersecretion disorder characterized by excessive tearing with gustatory stimulation while eating, drinking, or smelling food. Surgeons tend to overlook CTS after vestibular schwannoma (VS) surgery because its symptoms are less obvious compared with facial paralysis. The authors aim to elucidate the precise incidence and the detailed natural course of CTS after VS surgery. Methods This study included 128 consecutive patients with unilateral VSs resected via a retrosigmoid, lateral suboccipital approach. Clinical information on the patients was obtained by retrospective chart review. The presence of, time of onset of, and recovery of patients from CTS were obtained from the chart or evaluated from the most recent outpatient visit. Results A total of 14 patients (10.9%) developed CTS. Motor function of the facial nerve at discharge was statistically related to the occurrence of CTS (p < 0.001). The odds ratio of House-Brackmann Grade 4 compared with Grade 1 was 86.4 (p < 0.001). A bimodal distribution of CTS onset was observed, with a mean onset of 6.1 ± 4.0 months after resection. The CTS improved in 10 patients (71%) at various intervals, whereas CTS resolved in only 7 patients (50%) at a mean interval of 10.9 ± 7.9 months. The mean interval to recovery in the early-onset group was 9.7 ± 7.9 months, and it was 18 months in the late-onset group; the mean is given ± SD throughout. Conclusions The occurrence of CTS following VS surgery was more common than expected; however, a surgical procedure intended to protect the functioning of the facial nerve appears to be conducive to reduction of the occurrence of CTS. To reduce the distress caused by CTS, all patients should be given sufficient information and provide their informed consent prior to surgery.

PMID: 22304448 [PubMed - as supplied by publisher]

A novel technique of multiple-site epidural blood patch administration for the treatment of cerebrospinal fluid hypovolemia.

J Neurosurg. 2012 Feb 3;

Authors: Ohtonari T, Ota S, Nishihara N, Ota T, Tanaka Y, Sekihara Y, Tanaka A

Abstract

Object An epidural blood patch (EBP) is a widely accepted standard procedure to treat CSF hypovolemia, especially when the epidural CSF leak is detected by spinal MRI or CT myelography (CTM). In quite a few cases, however, the leaked CSF is spread over a large area along the spinal epidural space, making it difficult for the surgeon to clearly identify the true leakage points. In such cases, autologous blood can be infused at multiple spinal levels with multiple entries. In this paper, the authors have devised a new multiple-site EBP method with a single lumbar entry point by way of using an intravenous catheter as a slidable device for continuous infusion. In this report, they introduce this new, single-entry, continuous multiple-site EBP administration technique and report some of the results that they have obtained. Methods An EBP was applied via an epidural catheter in 5 patients with spontaneous CSF hypovolemia (3 men and 2 women; mean age 47.2 years, range 34-65 years). The detection of an epidural CSF leak was based on MRI and/or CTM findings. In all cases, however, the leakage sites could not be identified clearly. The main symptoms of these patients were recurrent spontaneous chronic subdural hematoma with orthostatic headache (3 patients) and orthostatic headache only (2 patients). All patients underwent surgery in the prone position on an angiography table, and biplane fluoroscopy was used for accurate manipulation. After administration of a local anesthetic, the authors inserted a 4-Fr short sheath (which is standard in angiography) through the lumbar interlaminar window and placed it in the dorsal epidural space. They then introduced a 4.2-Fr straight catheter through the sheath and navigated it upward along a 35-gauge guidewire whose tip was moved upward beyond the cranial end of the detected CSF leakage. Blood was obtained from each patient from a previously secured venous entry on the forearm, and it was injected slowly into the epidural catheter. Each time, the authors tried to infuse as much autologous blood as possible into the epidural space, while moving the catheter gradually in the caudal direction in response to the patient’s expression of pain. Results In all 3 cases of chronic subdural hematoma, its recurrence was prevented. In 1 patient, the orthostatic headache disappeared completely, and it was relieved in the other 4 patients. Conclusions An efficient treatment option for CSF hypovolemia is provided by the new application method of EBP with the aid of an intravenous catheter as a slidable device, which enables infusion of a sufficient amount of autologous blood into multiple epidural areas with a single lumbar entry point.

PMID: 22304449 [PubMed - as supplied by publisher]

Rates and predictors of long-term seizure freedom after frontal lobe epilepsy surgery: a systematic review and meta-analysis.

J Neurosurg. 2012 Feb 3;

Authors: Englot DJ, Wang DD, Rolston JD, Shih TT, Chang EF

Abstract

Object Frontal lobe epilepsy (FLE) is the second-most common focal epilepsy syndrome, and seizures are medically refractory in many patients. Although various studies have examined rates and predictors of seizure freedom after resection for FLE, there is significant variability in their results due to patient diversity, and inadequate follow-up may lead to an overestimation of long-term seizure freedom. Methods In this paper the authors report a systematic review and meta-analysis of long-term seizure outcomes and predictors of response after resection for intractable FLE. Only studies of at least 10 patients examining seizure freedom after FLE surgery with postoperative follow-up duration of at least 48 months were included. Results Across 1199 patients in 21 studies, the overall rate of postoperative seizure freedom (Engel Class I outcome) was 45.1%. No trend in seizure outcomes across all studies was observed over time. Significant predictors of long-term seizure freedom included lesional epilepsy origin (relative risk [RR] 1.67, 95% CI 1.36-28.6), abnormal preoperative MRI (RR 1.64, 95% CI 1.32-2.08), and localized frontal resection versus more extensive lobectomy with or without an extrafrontal component (RR 1.71, 95% CI 1.26-2.43). Within lesional FLE cases, gross-total resection led to significantly improved outcome versus subtotal lesionectomy (RR 1.99, 95% CI 1.47-2.84). Conclusions These findings suggest that FLE patients with a focal and identifiable lesion are more likely to achieve seizure freedom than those with a more poorly defined epileptic focus. While seizure freedom can be achieved in the surgical treatment of medically refractory FLE, these findings illustrate the compelling need for improved noninvasive and invasive localization techniques in FLE.

PMID: 22304450 [PubMed - as supplied by publisher]

Coexistence of intracranial aneurysm in 800 patients with surgically confirmed pituitary adenoma.

J Neurosurg. 2012 Feb 3;

Authors: Oh MC, Kim EH, Kim SH

Abstract

Object The purpose of this study was to assess factors associated with intracranial aneurysm (IA) in patients with pituitary adenoma (PA). In addition, these patients were compared with a control group from the general patient population in terms of the age-matched prevalence rate and the pattern of distribution of IA. Methods The authors retrospectively reviewed 800 patients who received transsphenoidal surgery for PA and 3850 control patients from the general patient population who were evaluated for routine health care at the authors’ institution between 2004 and 2010. All patients underwent MR imaging and MR angiography. Hormone assessment and pathological examination performed using immunohistochemical (IHC) staining were completed for patients with PA. Results Coexistence of IA in patients with PA was detected in 18 patients (2.3%). Multivariate analysis showed that age (p = 0.04) and cavernous sinus invasion (p < 0.001) were correlated with the increased incidence of IA, but hormone type, IHC staining, and sex were not associated. An age-matched comparison of the prevalence of IA showed an increased prevalence in patients with PA compared with the controls (p = 0.014), and when categorized according to age by decade, the 6th decade was significantly different (p = 0.039). However, the intracranial distribution pattern of IA did not demonstrate a significant difference. Conclusions Older age and the existence of a cavernous sinus invasion were correlated with increased incidence of IA in patients with PA. An age-matched comparison showed an increased incidence of IA in patients with PA than in the controls.

PMID: 22304451 [PubMed - as supplied by publisher]

Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas.

J Neurosurg. 2012 Feb 3;

Authors: Krieg SM, Shiban E, Buchmann N, Gempt J, Foerschler A, Meyer B, Ringel F

Abstract

Object Navigated transcranial magnetic stimulation (nTMS) is a newly evolving technique. Despite its supposed purpose (for example, preoperative central region mapping), little is known about its accuracy compared with established modalities like direct cortical stimulation (DCS) and functional MR (fMR) imaging. Against this background, the authors performed the current study to compare the accuracy of nTMS with DCS and fMR imaging. Methods Fourteen patients with tumors in or close to the precentral gyrus were examined using nTMS for motor cortex mapping, as were 12 patients with lesions in the subcortical white matter motor tract. Moreover, preoperative fMR imaging and intraoperative mapping of the motor cortex were performed via DCS, and the outlining of the motor cortex was compared. Results In the 14 cases of lesions affecting the precentral gyrus, the primary motor cortex as outlined by nTMS correlated well with that delineated by intraoperative DCS mapping, with a deviation of 4.4 ± 3.4 mm between the two methods. In comparing nTMS with fMR imaging, the deviation between the two methods was much larger: 9.8 ± 8.5 mm for the upper extremity and 14.7 ± 12.4 mm for the lower extremity. In 13 of 14 cases, the surgeon admitted easier identification of the central region because of nTMS. The procedure had a subjectively positive influence on the operative results in 5 cases and was responsible for a changed resection strategy in 2 cases. One of 26 patients experienced nTMS as unpleasant; none found it painful. Conclusions Navigated TMS correlates well with DCS as a gold standard despite factors that are supposed to contribute to the inaccuracy of nTMS. Moreover, surgeons have found nTMS to be an additional and helpful modality during the resection of tumors affecting eloquent motor areas, as well as during preoperative planning.

PMID: 22304452 [PubMed - as supplied by publisher]

Letter to the Editor: Deep brain stimulation and hemorrhage.

J Neurosurg. 2012 Feb 3;

Authors: Bakay RA, Vannemreddy PS

PMID: 22304469 [PubMed - as supplied by publisher]

Salvage Hepatectomy for Local Recurrent Hepatocellular Carcinoma After Ablation Therapy.

Ann Surg Oncol. 2012 Feb 1;

Authors: Sugo H, Ishizaki Y, Yoshimoto J, Imamura H, Kawasaki S

Abstract

BACKGROUND: The results of salvage hepatectomy for local recurrent hepatocellular carcinoma after incomplete percutaneous ablation therapy are still unclear. METHODS: We conducted a retrospective analysis of 197 consecutive patients with hepatocellular carcinoma who underwent either salvage hepatectomy after prior incomplete percutaneous ablation therapy (salvage group; n = 23) or primary hepatectomy as the initial treatment (primary group; n = 174). The two groups were compared with respect to intraoperative data, operative mortality and morbidity, and long-term survival. RESULTS: The salvage group showed a significantly longer operation time (385 vs. 300 min; P = 0.006) and a significantly greater intraoperative blood loss volume (402 vs. 265 ml; P = 0.024). The postoperative mortality rate was zero in both groups, and the morbidity rates were similar. Although the 1-, 3-, and 5-year disease-free survival rates after hepatectomy were significantly worse in the salvage group than in the primary group (65%, 41%, and 33% vs. 81%, 51%, and 45%, respectively; P = 0.031), the overall survival rates after hepatectomy did not differ significantly (91%, 91%, and 67% vs. 96%, 79%, and 65%, respectively; P = 0.790). The 1-, 3-, and 5-year overall survival and disease-free survival rates after percutaneous ablation therapy were also not different from those in the primary group (100, 96, and 83%, P = 0.115; and 96, 60, and 45%, P = 0.524, respectively). CONCLUSIONS: The short-term and long-term results of salvage hepatectomy after incomplete percutaneous ablation therapy are equivalent to those of primary hepatectomy. Salvage hepatectomy is an acceptable treatment for patients with local recurrence of hepatocellular carcinoma after ablation therapy.

PMID: 22302262 [PubMed - as supplied by publisher]

The Relationship of Lymph Node Evaluation and Colorectal Cancer Survival After Curative Resection: A Multi-Institutional Study.

Ann Surg Oncol. 2012 Feb 1;

Authors: Kanemitsu Y, Komori K, Ishiguro S, Watanabe T, Sugihara K

Abstract

PURPOSE: This multicenter retrospective study aimed to clarify whether the number of lymph nodes retrieved influenced staging and survival in colorectal cancer. METHODS: We evaluated a total of 4538 patients who underwent curative resection for colorectal cancer with stage I, stage II, and stage III. RESULTS: The median number of lymph nodes retrieved was 19. The 5-year actuarial disease-specific survival of colon cancer patients with stage I, stage II, and stage III was 99.0%, 94.1%, and 79.1%, respectively, and that for rectal cancer patients with stage I, stage II, and stage III was 98.2%, 88.3%, and 69.1%, respectively. After adjustment for confounders, the number of lymph nodes retrieved and the number of positive nodes were both significant in prognosis for patients with colon cancer and rectal cancer. Survival improved with an increasing number of nodes in stage II patients. In stage III, patients within strata of retrieval of fewer than 12 nodes with a cutoff based on quartiles had lower discriminative ability (c-index 0.683). Patients who were treated at the hospitals with higher average node counts (>23.4 nodes) and higher 12-node measure compliance (>80%) experienced better survival than those treated at the hospitals with lower average node counts for advanced T-stage. CONCLUSION: This study found that the number of lymph nodes retrieved and the number of positive nodes are both important prognostic factors. At least a 12-node threshold may be supported as a measure to improve a predictive capacity within individual patients and as a quality control parameter of hospital performance.

PMID: 22302263 [PubMed - as supplied by publisher]

Comparison Between Radical Esophagectomy and Definitive Chemoradiotherapy in Patients with Clinical T1bN0M0 Esophageal Cancer.

Ann Surg Oncol. 2012 Feb 1;

Authors: Motoori M, Yano M, Ishihara R, Yamamoto S, Kawaguchi Y, Tanaka K, Kishi K, Miyashiro I, Fujiwara Y, Shingai T, Noura S, Ohue M, Ohigashi H, Nakamura S, Ishikawa O

Abstract

BACKGROUND: Esophagectomy remains the mainstay treatment for clinical T1bN0M0 esophageal cancer because pathologic lymph node metastases in these patients are not negligible. Recently, chemoradiotherapy (CRT), which can preserve the esophagus, has been reported to be a promising therapeutic alternative to esophagectomy. However, to our knowledge, no comparative studies of esophagectomy and CRT have been reported in clinical T1bN0M0 esophageal cancer. METHODS: A total of 173 patients with clinical T1bN0M0 squamous cell carcinoma of the thoracic esophagus were enrolled in this study, 102 of whom were treated with radical esophagectomy (S group) and 71 with definitive CRT (CRT group). Treatment results of both groups were retrospectively compared. RESULTS: No statistically significant difference was found in overall survival, but the S group displayed significantly better progression-free survival than the CRT group. Disease recurrence was observed in 12 S group patients and 20 CRT group patients. The incidence of distant recurrence was similar, while local recurrence and lymph node recurrence were significantly more frequent in the CRT group. In the S group, 20 patients had pathologic lymph node metastasis. The progression-free survival of patients with pathologic lymph node metastasis did not differ from those without nodal metastasis. In the CRT group, local recurrence could be controlled by salvage esophagectomy, but treatment results of lymph node recurrence were poor; only 4 of 12 patients with lymph node recurrences were cured. CONCLUSIONS: Selection of patients at high risk of pathologic lymph node metastasis is essential when formulating treatment decisions for clinical T1bN0M0 esophageal cancers.

PMID: 22302264 [PubMed - as supplied by publisher]

Combined Diffusion-Weighted and Gadolinium-Enhanced MRI Can Accurately Predict the Peritoneal Cancer Index Preoperatively in Patients Being Considered for Cytoreductive Surgical Procedures.

Ann Surg Oncol. 2012 Feb 3;

Authors: Low RN, Barone RM

Abstract

PURPOSE: To determine whether abdominal and pelvic magnetic resonance imaging (MRI) with diffusion-weighted and dynamic gadolinium-enhanced imaging can be used to accurately calculate the peritoneal cancer index (PCI) before surgery compared to the PCI tabulated at surgery. METHODS: Thirty-three patients underwent preoperative MRI followed by cytoreductive surgery for primary tumors of the appendix (n = 25), ovary (n = 5), colon (n = 2), and mesothelioma (n = 1). MRIs were retrospectively reviewed to determine the MRI PCI. These scores were then compared to PCI tabulated at surgery. Patients were categorized as having small-volume tumors (PCI 0-9), moderate-volume tumors (PCI 10-20), and large-volume tumors (PCI > 20). The respective anatomic site scores for both MRI and surgery were compared. RESULTS: There was no significant difference between the MRI PCI and surgical PCI for the 33 patients (P = 0.12). MRI correctly predicted the PCI category in 29 (0.88) of 33 patients. Compared to surgical findings, MRI correctly predicted small-volume tumor in 6 of 7 patients, moderate-volume tumor in 3 of 4 patients, and large-volume tumor in 20 of 22 patients. MRI and surgical PCI scores were identical in 8 patients (24%). A difference of <5 was noted in 16 patients (49%) and of 5-10 in 9 patients (27%). Compared to surgical-site findings, MRI depicted 258 truly positive sites of peritoneal tumor, 35 falsely negative sites, 35 falsely positive sites, and 101 truly negative sites, with a corresponding sensitivity of 0.88, specificity of 0.74, and accuracy of 0.84. CONCLUSIONS: Combined diffusion-weighted and gadolinium-enhanced peritoneal MRI accurately predicts the PCI before surgery in patients undergoing evaluation for cytoreductive surgery.

PMID: 22302265 [PubMed - as supplied by publisher]

Cytoreductive Surgery with Selective Versus Complete Parietal Peritonectomy Followed by Hyperthermic Intraperitoneal Chemotherapy in Patients with Diffuse Malignant Peritoneal Mesothelioma: A Controlled Study.

Ann Surg Oncol. 2012 Feb 3;

Authors: Baratti D, Kusamura S, Cabras AD, Deraco M

Abstract

BACKGROUND: Combined treatment involving peritonectomy procedures, multivisceral resections, and hyperthermic intraperitoneal chemotherapy (HIPEC) has reportedly resulted in survival benefit for peritoneal surface malignancies, including diffuse malignant peritoneal mesothelioma (DMPM). Many unanswered questions remain regarding the surgical options in the management of DMPM. The aim of this case-control study was to assess the impact of the type and extent of parietal peritonectomy on survival and operative outcomes. METHODS: Thirty patients with DMPM undergoing selective parietal peritonectomy (SPP) of macroscopically involved regions, and 30 matched patients undergoing routine complete parietal peritonectomy (CPP), regardless of disease distribution, were retrospectively identified from a prospective database. RESULTS: Groups were comparable for all characteristics, except for a higher proportion of patients treated before July 2003 and undergoing preoperative systemic chemotherapy in the SPP group. Median follow-up was 86.2 months in the SPP group and 50.3 months in the CPP group. Median overall survival was 29.6 months in the SPP group and not reached in the CPP group; 5-year overall survival was 40.0% and 63.9%, respectively (P = 0.0269). At multivariate analysis, CPP versus SPP was recognized as an independent predictor of better prognosis, along with complete cytoreduction, negative lymph nodes, epithelial histology, and lower MIB-1 labelling index. Morbidity and reoperation rates were not different between groups. No operative mortality occurred. In 12 of 24 patients undergoing CPP, pathologic examination detected disease involvement on parietal surfaces with no evident tumor at surgical exploration. CONCLUSIONS: CPP improved survival in patients with DMPM undergoing combined treatment. This information may contribute to standardize surgical options for DMPM and other peritoneal malignancies.

PMID: 22302266 [PubMed - as supplied by publisher]

Importance of Histologic Subtype in the Staging of Appendiceal Tumors.

Ann Surg Oncol. 2012 Feb 3;

Authors: Turaga KK, Pappas SG, Gamblin TC

Abstract

BACKGROUND: Malignant neoplasms of the appendix have different behavior based on their histologic subtypes in anecdotal series. Current staging systems do not capture the diversity of histologic subtypes in predicting outcomes. METHODS: We queried all patients with appendiceal malignancies captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Tumors were classified as colonic type adenocarcinoma, mucinous adenocarcinoma, signet ring cell type, goblet cell carcinoid, and malignant carcinoid. We compared incidence, overall survival, and disease-specific survival for these tumors on the basis of patient, tumor, and therapy characteristics. Estimates from Cox proportional hazard modeling were used to predict hazard ratios for differing histologic subtypes with similar tumor, node, metastasis system (TNM) stages. RESULTS: Of the 5672 patients identified, we included 5655 (99%) in our analysis. The 5-year disease-specific survival rates were 93% for malignant carcinoid, 81% for goblet cell carcinoid, 55% for colonic type adenocarcinoma, 58% for mucinous adenocarcinoma, and 27% for signet ring cell type. Predicted estimates of adjusted hazard ratios revealed an 8-fold difference between histologic subtypes for similar TNM stages. CONCLUSIONS: Histologic subtype is an important predictor of disease-specific survival and overall survival in patients with appendiceal neoplasms. Addition of the histologic subtype to the TNM staging is simple and may improve prognostication.

PMID: 22302267 [PubMed - as supplied by publisher]

Quality of Life Outcomes after Isolated Limb Infusion.

Ann Surg Oncol. 2012 Feb 3;

Authors: McClaine RJ, Giglia JS, Ahmad SA, McCoy SJ, Sussman JJ

Abstract

BACKGROUND: Isolated limb infusion (ILI) for the treatment of in-transit melanoma was originally described more than 10 years ago. Response rates of 45-53% have been reported in U.S. series. Long-term quality of life outcomes after this procedure have not been described. We hypothesized that ILI is rarely associated with long-term limb morbidity. METHODS: ILIs performed at our institution between July 2005 and June 2009 were reviewed. Patients were contacted cross-sectionally at 2 time points. During these interviews, response to treatment and postoperative limb function were assessed. RESULTS: Thirty-two ILIs were performed during the time period. Twenty-seven patients were treated for in-transit melanoma; 5 were treated for recurrent Merkel cell carcinoma. The 30-day mortality was 0%. Three patients (9%) required fasciotomy. Durable complete responses were achieved in 41% of patients, with mean follow-up time of 19.4 ± 9.6 months after infusion; after this period, 53% reported progression of disease. The most common postprocedure symptoms were edema (88%), numbness (59%), and pain (59%). By 3 months and at the time of last follow-up, the most common symptoms were edema (82%), numbness (65%), and stiffness (35%). No patients reported impaired limb function at the time of last follow-up compared to baseline. Median survival was 19.2 ± 4.2 months after infusion. CONCLUSIONS: ILI for melanoma and Merkel cell carcinoma is associated with postprocedure symptoms in most patients, most commonly edema, color change, and numbness. At last follow-up, no ILI patients had residual functional impairment in the treated limb.

PMID: 22302268 [PubMed - as supplied by publisher]

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Sarcomatosis.

Ann Surg Oncol. 2012 Feb 3;

Authors: Salti GI, Ailabouni L, Undevia S

Abstract

BACKGROUND: The prognosis of peritoneal sarcomatosis is generally poor and conventional treatments for this disease process are mostly ineffective. The use of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as an aggressive locoregional treatment option remains controversial. METHODS: We reviewed 13 patients with peritoneal sarcomatosis who underwent CRS and closed-abdomen HIPEC with cisplatin and doxorubicin between March 2007 and March 2010. None of the patients was diagnosed with GIST or uterine leiomyosarcoma. Both disease-free survival (DFS) and overall survival (OS) were evaluated. Completeness of cytoreduction (CC) and peritoneal cancer index (PCI) were assessed. RESULTS: There was no operative mortality. Median follow-up was 12 (range, 4-43) months. Peritoneal disease progression occurred in six patients, distant metastases alone in none, and both in two patients. Median DFS and OS were 11 and 12 months, respectively. Completeness of cytoreduction significantly affected survival. Mean DFS and OS in those patients where a CC-0 was achieved was 27.25 ± 5.71 (median, 20) months and 35.25 ± 4.75 months (median, not reached). In contrast, patients with gross residual disease (CC ≥ 1) had a DFS of 4.25 ± 1.43 months (median, 4 months; P = 0.03) and an OS of 5.25 ± 2.36 months (median, 4 months; P = 0.02). In addition, PCI influenced survival when evaluated by univariate analysis. Using multivariate analysis, completeness of cytoreduction was the only covariate influencing overall survival (P = 0.012). CONCLUSIONS: A complete cytoreduction and low PCI score appear to be important factors in considering CRS and HIPEC for patients with peritoneal sarcomatosis.

PMID: 22302269 [PubMed - as supplied by publisher]

Aggressive Management of Peritoneal Carcinomatosis from Mucinous Appendiceal Neoplasms.

Ann Surg Oncol. 2012 Feb 3;

Authors: Austin F, Mavanur A, Sathaiah M, Steel J, Lenzner D, Ramalingam L, Holtzman M, Ahrendt S, Pingpank J, Zeh HJ, Bartlett DL, Choudry HA

Abstract

BACKGROUND: Peritoneal carcinomatosis (PC) in the setting of mucinous appendiceal neoplasms is characterized by the intraperitoneal accumulation of mucinous ascites and mucin-secreting epithelial cells that leads to progressive compression of intra-abdominal organs, morbidity, and eventual death. We assessed postoperative and oncologic outcomes after aggressive surgical management by experienced surgeons. METHODS: We analyzed clinicopathologic, perioperative, and oncologic outcome data in 282 patients with PC from appendiceal adenocarcinomas between 2001 and 2010 from a prospective database. Kaplan-Meier survival curves and multivariate Cox-regression models were used to identify prognostic factors affecting oncologic outcomes. RESULTS: Adequate cytoreduction was achieved in 82% of patients (completeness of cytoreduction score (CC)-0: 49%; CC-1: 33%). Median simplified peritoneal cancer index (SPCI), operative time, and estimated blood loss were 14 (range, 0-21), 483.5 min (range, 46-1,402), and 800 ml (range, 0-14,000), respectively. Pathology assessment demonstrated high-grade tumors in 36% of patients and lymph node involvement in 23% of patients. Major postoperative morbidity occurred in 70 (25%) patients. Median overall survival was 6.72 years (95% confidence interval (CI), 4.17 years not reached), with 5 year overall survival probability of 52.7% (95% CI, 42.4, 62%). In a multivariate Cox-regression model, tumor grade, age, preoperative SPCI and chemo-naïve status at surgery were joint significant predictors of overall survival. Tumor grade, postoperative CC-score, prior chemotherapy, and preoperative SPCI were joint significant predictors of time to progression. CONCLUSIONS: Aggressive management of PC from mucinous appendiceal neoplasms, by experienced surgeons, to achieve complete cytoreduction provides long-term survival with low major morbidity.

PMID: 22302270 [PubMed - as supplied by publisher]

Chronic Anti-inflammatory Drug Therapy Inhibits Gel-Forming Mucin Production in a Murine Xenograft Model of Human Pseudomyxoma Peritonei.

Ann Surg Oncol. 2012 Feb 3;

Authors: Choudry HA, Mavanur A, O’Malley ME, Zeh HJ, Sheng Guo Z, Bartlett DL

Abstract

BACKGROUND: Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP. METHODS: The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays. RESULTS: Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count. CONCLUSIONS: Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.

PMID: 22302271 [PubMed - as supplied by publisher]

Concepts of Regional Therapies for Advanced Malignancy.

Ann Surg Oncol. 2012 Feb 3;

Authors: Gamblin TC, Alexander HR, Edwards R, Bartlett DL

PMID: 22302272 [PubMed - as supplied by publisher]

Erratum to: The Combination of Surgery and Imatinib in GIST: A Reality for Localized Tumors at High Risk, an Open Issue for Metastatic Ones.

Ann Surg Oncol. 2012 Feb 1;

Authors: Gronchi A, Raut CP

PMID: 22302273 [PubMed - as supplied by publisher]

IRE1α activation protects mice against acetaminophen-induced hepatotoxicity.

J Exp Med. 2012 Jan 30;

Authors: Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH

Abstract

The mammalian stress sensor IRE1α plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1α can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1α in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1α activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1α suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1α-deficient mouse liver, indicating the essential role of IRE1α in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism.

PMID: 22291093 [PubMed - as supplied by publisher]

Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine.

J Exp Med. 2012 Jan 30;

Authors: Shaw MH, Kamada N, Kim YG, Núñez G

Abstract

T(H)17 cells are a lineage of CD4(+) T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of T(H)17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal T(H)17 (sT(H)17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sT(H)17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sT(H)17 cells. In the absence of IL-1β-IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sT(H)17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88-deficient (MyD88(-/-)) and germ-free (GF) mice, but not IL-1R(-/-) mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R-expressing T cells to drive the generation of sT(H)17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor-related orphan receptor γt-expressing sT(H)17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sT(H)17 differentiation in the intestine, which may have therapeutic implications for T(H)17-mediated pathologies.

PMID: 22291094 [PubMed - as supplied by publisher]

FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination.

J Exp Med. 2012 Jan 30;

Authors: Alkhatib A, Werner M, Hug E, Herzog S, Eschbach C, Faraidun H, Köhler F, Wossning T, Jumaa H

Abstract

Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Using pro-B cells lacking the phosphatase Pten (phosphatase and tensin homolog), which negatively regulates phosphoinositide-3-kinase (PI3K) signaling, we show that PI3K signaling inhibits Ig gene rearrangement by suppressing the expression of the transcription factor Ikaros. Further analysis revealed that the transcription factor FoxO1 is crucial for Ikaros expression and that PI3K-mediated down-regulation of FoxO1 suppresses Ikaros expression. Interestingly, FoxO1 did not influence Ikaros transcription; instead, FoxO1 is essential for proper Ikaros mRNA splicing, as FoxO1-deficient cells contain aberrantly processed Ikaros transcripts. Moreover, FoxO1-induced Ikaros expression was sufficient only for proximal V(H) to DJ(H) gene rearrangement. Simultaneous expression of the transcription factor Pax5 was needed for the activation of distal V(H) genes; however, Pax5 did not induce any Ig gene rearrangement in the absence of Ikaros. Together, our results suggest that ordered Ig gene rearrangement is regulated by distinct activities of Ikaros, which mediates proximal V(H) to DJ(H) gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal V(H) genes.

PMID: 22291095 [PubMed - as supplied by publisher]

Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury.

J Exp Med. 2012 Jan 30;

Authors: Block H, Herter JM, Rossaint J, Stadtmann A, Kliche S, Lowell CA, Zarbock A

Abstract

Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain-containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin-mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion-induced AKI in mice. By using genetically engineered mice and transduced Slp76(-/-) primary leukocytes, we demonstrate that ADAP as well as two N-terminal-located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kγ (phosphoinositide 3-kinase-γ)- and PLCγ2 (phospholipase Cγ2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin-mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion-induced AKI in humans.

PMID: 22291096 [PubMed - as supplied by publisher]

What’s Hot in the Red Journal This Month.

Am J Gastroenterol. 2012 Feb;107(2):151-3

Authors:

PMID: 22306936 [PubMed - in process]

Use of a screening tool to determine nonadherent behavior in inflammatory bowel disease.

Am J Gastroenterol. 2012 Feb;107(2):154-60

Authors: Kane S, Becker B, Harmsen WS, Kurian A, Morisky DE, Zinsmeister AR

Abstract

OBJECTIVES: Nonadherence is an issue in the management of inflammatory bowel disease (IBD), and no validated screening tool is available. We aimed to determine whether scores from a self-reported adherence survey correlated with pharmacy refill data as a reliable measure of medication adherence.

METHODS: We used the eight item, self-reported Morisky Medication Adherence Scale. Each question is worth a point, with a maximum score of 8. Pharmacies were contacted for refill information for the previous 3 months, then 3 and 6 months from enrollment. Refill data were recorded for each time interval as the medication possession ratio (MPR); adherence was defined as >80%. Analysis of variance was used to determine the relationship between survey scores and MPR by drug class.

RESULTS: One hundred fifty outpatients were enrolled, of whom 94 had Crohn’s disease and 56 had ulcerative colitis; 89 were female. At baseline, 47% of patients were on 5-aminosalicylic acid (5-ASA), 54% an immunomodulator, 15% infliximab, 8% an injectable biologic, and 6% budesonide. The median adherence score was 7. Fifty-two percent stated they “rarely” missed a dose of medication. The median adherence score, as defined by refill data, ranged from 0% (injectable biologic) to 75% (infliximab) by drug class. Only those on an immunomodulator had a survey score that positively correlated with adherence.

CONCLUSIONS: Only those on a thiopurine were likely to have a score predicting adherence behavior. Adherence to therapy for IBD is complex and cannot be predicted reliably by a self-reported survey tool validated for other chronic conditions.

PMID: 22306937 [PubMed - in process]

Darwinian dyspepsia: an extraordinary scientist, an ordinary illness, great dignity.

Am J Gastroenterol. 2012 Feb;107(2):161-4

Authors: Shanahan F

PMID: 22306938 [PubMed - in process]

Images of the month.

Am J Gastroenterol. 2012 Feb;107(2):165

Authors:

PMID: 22306939 [PubMed - in process]

Continuing medical education: february 2012.

Am J Gastroenterol. 2012 Feb;107(2):166

Authors:

PMID: 22306940 [PubMed - in process]

Continuing medical education questions: february 2012.

Am J Gastroenterol. 2012 Feb;107(2):177

Authors: Devault KR, Patel MK, Qumseya B

PMID: 22306941 [PubMed - in process]

Continuing medical education: february 2012.

Am J Gastroenterol. 2012 Feb;107(2):178

Authors:

PMID: 22306942 [PubMed - in process]

Continuing medical education questions: february 2012.

Am J Gastroenterol. 2012 Feb;107(2):195

Authors: Devault KR, Cooney W, Prabhu A

PMID: 22306943 [PubMed - in process]

Editorial: Serum IGF-1 Linking Visceral Obesity With Esophageal Adenocarcinoma: Unconvincing Evidence.

Am J Gastroenterol. 2012 Feb;107(2):205-6

Authors: McColl KE

Abstract

There is a strong positive association between body mass index (BMI) and risk of esophageal adenocarcinoma. This is likely to be largely or entirely explained by the established association between central obesity and gastroesophageal reflux and between the latter and risk of esophageal adenocarcinoma. Visceral fat is also metabolically active and there is interest in the possibility that humoral factors released by this fat might promote esophageal carcinogenesis. Insulin growth factor I (IGF-1) has been studied but current data do not support circulating total IGF-1 as a humoral factor linking BMI and esophageal carcinogenesis.

PMID: 22306944 [PubMed - in process]

Editorial: Abnormal Immune Regulation and Low-Grade Inflammation in IBS: Does One Size Fit All?

Am J Gastroenterol. 2012 Feb;107(2):273-5

Authors: Schmulson M, Chey WD

Abstract

Evidences suggest that there is low-grade inflammation in the colonic mucosa and/or a state of immune activation in patients with irritable bowel syndrome (IBS). Results from available studies are inconsistent mainly because of differences in measures, methodologies and study populations. In this issue, Chang et al. evaluated a comprehensive set of cytokines, immune markers and immune-related cells in patients with non post infectious IBS (non PI-IBS) and controls. The main finding was a lower expression of the mRNA of the anti-inflammatory IL-10 cytokine in the colonic mucosa of women with non PI-IBS without any differences in the cell counts. These results suggest that in non PI-IBS, there is altered immune regulation/activation without evidence of low-grade mucosal inflammation. Further, PI and non PI-IBS may be associated with different alterations in immune function/activation.

PMID: 22306945 [PubMed - in process]

Editorial: Pancreas Divisum Does Not Cause Pancreatitis, But Associates With CFTR Mutations.

Am J Gastroenterol. 2012 Feb;107(2):318-20

Authors: Dimagno MJ, Dimagno EP

Abstract

Bertin et al. partially dispel arguments that pancreas divisum (PD) causes pancreatitis, but fascinatingly indicate that PD associates with CFTR gene mutations predisposing to pancreatitis. This association, however, does not definitely confer a pathophysiological role for PD in pancreatitis but may denote that PD co-mingles with CFTR mutations without influencing pancreatitis or CFTR mutations influence pancreatic duct embryogenesis. We advise “idiopathic pancreatitis” patients with PD to undergo genetic testing. In lieu of CFTR mutations undertake no endoscopic/surgical procedure; if CFTR mutations are found, then refer patients for genetic counseling and withhold endoscopic/surgical therapy unless randomized studies show benefit.

PMID: 22306946 [PubMed - in process]

Efficacy of certolizumab pegol in Crohn’s disease: response to ford et Al.

Am J Gastroenterol. 2012 Feb;107(2):321

Authors: Kayhan C, Pierre-Louis B, Sen D, Serna M

PMID: 22306947 [PubMed - in process]

Response to kayhan et Al.

Am J Gastroenterol. 2012 Feb;107(2):321-2

Authors: Ford AC, Moayyedi P

PMID: 22306948 [PubMed - in process]

GERD Diagnosis: Pretest Probability and the “Gold” Standard Alter Outcome.

Am J Gastroenterol. 2012 Feb;107(2):322-3

Authors: Vakil N, Kahrilas PJ

PMID: 22306949 [PubMed - in process]

Response to vakil and kahrilas.

Am J Gastroenterol. 2012 Feb;107(2):323-4

Authors: Lacy BE, Chehade R, Crowell MD

PMID: 22306950 [PubMed - in process]

Inflammatory Bowel Disease: Relevant History-Taking Is More Important Than Routine HIV Testing.

Am J Gastroenterol. 2012 Feb;107(2):324

Authors: Ngiu CS

PMID: 22306951 [PubMed - in process]

HIV Test Is More Reliable Than Self-Report on Risk Behaviors: Response to Chai-Soon Ngiu.

Am J Gastroenterol. 2012 Feb;107(2):324-5

Authors: Soria A, Rossi M, Muscatello A, Gori A

PMID: 22306952 [PubMed - in process]

Withdrawing PPI Therapy: Response to Metz et al.

Am J Gastroenterol. 2012 Feb;107(2):325-6

Authors: Waldum HL, Sandvik AK, Hauso O, Qvigstad G, Fossmark R

PMID: 22306953 [PubMed - in process]

Response to waldum et Al.

Am J Gastroenterol. 2012 Feb;107(2):326

Authors: Metz DC, Pilmer BL, Han C, Perez MC

PMID: 22306954 [PubMed - in process]

Usefulness of 4D MRI Flow Imaging to Control TIPS Function.

Am J Gastroenterol. 2012 Feb;107(2):327-8

Authors: Stankovic Z, Blanke P, Markl M

PMID: 22306955 [PubMed - in process]

How early should endoscopy be performed in suspected upper gastrointestinal bleeding?

Am J Gastroenterol. 2012 Feb;107(2):328-9

Authors: Barkun AN, Bardou M, Kuipers EJ, Sung J

PMID: 22306956 [PubMed - in process]

Calendar of courses, symposiums, and conferences.

Am J Gastroenterol. 2012 Feb;107(2):330

Authors:

PMID: 22306957 [PubMed - in process]

Erratum: comparison of guaiac-based and quantitative immunochemical fecal occult blood testing in a population at average risk undergoing colorectal cancer screening.

Am J Gastroenterol. 2012 Feb;107(2):331-2

Authors: Park DI, Ryu S, Kim YH, Lee SH, Lee CK, Eun CS, Han DS

PMID: 22306958 [PubMed - in process]

Role of aortic stent graft oversizing and barb characteristics on folding.

J Vasc Surg. 2012 Feb 1;

Authors: Lin KK, Kratzberg JA, Raghavan ML

Abstract

OBJECTIVE: To evaluate folding in infrarenal stent grafts in relation to oversizing, barb angle, and barb length using computed tomography images of stent grafts deployed in explanted bovine aortas. METHODS: Computed tomography data from an in vitro investigation on the effect of oversizing of 4% to 45% (n = 19), barb length of 2 to 7 mm (n = 11), and barb angle of 10° to 90° (n = 7) on device fixation were examined for instances of folding. Folding was classified as circumferential or longitudinal and quantified on an ordinal scale based on codified criteria. Cumulative fold ranking from 0 (no fold) to 6 (two severe folds) for each deployment was used as the measure of folding observed. RESULTS: Of the 37 cases, cumulative mean ± standard deviation fold ranking for stent grafts oversized >30% (n = 5) was significantly greater than the rest (3.4 ± 1.7 vs 0.5 ± 1.2, respectively; Mann-Whitney U test; P < .005). When barb length was varied from 2 to 7 mm (oversizing held at 10%-20%), folding was noted in one of 11 cases. Similarly, when barb angle was varied from 0° (vertical) to 90° (horizontal), folding was not noted in any of the seven cases. The pullout force was not significantly different between stent grafts with and without folding (5.4 ± 1.95 vs 5.12 ± 1.89 N, respectively; P > .5). At least one instance of folding was noted in the seven of seven (100%) stent grafts with oversizing >23.5% and in only five of 30 (14%) stent grafts with oversizing <23.5%. CONCLUSIONS: Stent graft folding was prevalent when oversized >30%. Large variations in barb length and angle did not aggravate folding risk when oversized within the recommended range of 10% to 20%.

PMID: 22305271 [PubMed - as supplied by publisher]

Elective sac perfusion to reduce the risk of neurologic events following endovascular repair of thoracoabdominal aneurysms.

J Vasc Surg. 2012 Feb 1;

Authors: Harrison SC, Agu O, Harris PL, Ivancev K

Abstract

Spinal cord ischemia (SCI) is a catastrophic complication of thoracoabdominal aortic aneurysm (TAAA) repair. This article describes our early experience with a technique for maintaining perfusion of segmental vessels (intercostals and lumbars) in the early postoperative period after endovascular repair of a TAAA, with “sac perfusion branches” added to custom-made stent grafts. These are closed 7 to 10 days after the first procedure to complete exclusion of the aneurysm. We have used this technique in 10 patients with type II TAAAs. One developed monoparesis of the right leg during a period of hypotension secondary to a cardiac event and died within 30 days. Two patients developed lower limb weakness after closure of the perfusion branches, both with full recovery. Controlled perfusion of segmental vessels with perfusion branches is feasible and may be a useful adjunct to prevent SCI, providing protection to spinal cord perfusion during the immediate postoperative period when risk of SCI is greatest.

PMID: 22305272 [PubMed - as supplied by publisher]

Circulating microparticles and endothelial progenitor cells in atherosclerosis; pharmacological effects of irbesartan.

J Thromb Haemost. 2012 Feb 3;

Authors: Georgescu A, Alexandru N, Andrei E, Titorencu I, Dragan E, Tarziu C, Ghiorghe S, Badila E, Bartos D, Popov D

Abstract

Aims: This study aimed to (a) employ our newly designed model, the hypertensive-hypercholesterolemic hamster (HH) in order to find whether a correlation exist between circulating microparticles (MPs), endothelial progenitor cells (EPCs) and their contribution to vascular dysfunction and (b) to assess the effect of irbesartan treatment on HH animals (HHI). Methods and Results: The results showed that compared to control (C) group, HH displayed: (i) a significantly increase in plasma cholesterol and triglyceride concentration, and an augmentation of systolic and diastolic arterial blood pressure, and of heart rate; (ii) a marked elevation of MPs and a significant decrease in EPCs; (iii) structural modifications of arterial wall correlated with altered protein expression of MMP2, MMP9, MMP12, TIMP1, TIMP2 and collagen type I and III; (iv) a considerably altered reactivity of arterial wall closely correlated with MPs and EPC adherence; (v) an inflammatory process characterised by augmented expression of P-Selectin, E-Selectin, vWF, TF, IL-6, MCP-1, RANTES. Additionally, the experiments showed the potential of irbesartan to correct all altered parameters in HH and to mobilize EPCs by NO, chemokines and adhesion molecules dependent mechanism. Conclusions: Hypertension associated with hypercholesterolemia is accompanied by structural modifications and expression of pro-inflammatory molecules by vessel wall, the alteration of vascular tone, enhanced release of MPs and reduced EPCs; the ratio between the latter two may be considered as a marker of vascular dysfunction. Irbesartan that exhibit a pharmacological control on the levels of MPs and EPCs has the potential to restore homeostasis of the arterial wall.

PMID: 22303879 [PubMed - as supplied by publisher]

The Motivations and Experiences of Living Kidney Donors: A Thematic Synthesis.

Am J Kidney Dis. 2012 Feb 3;

Authors: Tong A, Chapman JR, Wong G, Kanellis J, McCarthy G, Craig JC

Abstract

BACKGROUND: Living kidney donation is associated with better recipient outcomes compared with deceased kidney donation, but living kidney donors face the risk of physical and psychological complications. The aim of this study was to synthesize published qualitative studies of the experiences and perspectives of living kidney donors. METHODS: We conducted a systematic review and thematic synthesis of qualitative studies of motivations to donate and experiences after donation of living kidney donors. MEDLINE, Embase, PsycINFO, CINAHL, and reference lists of articles were searched to April 2011. RESULTS: 26 studies involving 478 donors were included. We identified 6 themes about the decision to donate: compelled altruism, inherent responsibility, accepting risks, family expectation, personal benefit, and spiritual confirmation. Three themes dominated the impact of donation and postdonation: renegotiating identity (including subthemes of fear and vulnerability, sense of loss, depression and guilt, new appreciation of life, and personal growth and self-worth), renegotiating roles (including subthemes of multiplicity of roles, unable to resume previous activities, and hero status), and renegotiating relationships (including subthemes of neglect, proprietorial concern, strengthened family and recipient bonds, and avoidance of recipient indebtedness). CONCLUSIONS: Kidney donation has a profound and multifaceted impact on the lives of donors and requires them to renegotiate their identity, roles, and relationships. Strategies to safeguard against unwarranted coercion, and to maximize donor resilience, capacity to negotiate their multiple roles as a patient and carer, emotional fortitude, and ability to have balanced expectations and relationships with the recipient and the family are needed to ultimately protect the safety and well-being of living kidney donors.

PMID: 22305757 [PubMed - as supplied by publisher]

Novel Markers of Kidney Function as Predictors of ESRD, Cardiovascular Disease, and Mortality in the General Population.

Am J Kidney Dis. 2012 Feb 3;

Authors: Astor BC, Shafi T, Hoogeveen RC, Matsushita K, Ballantyne CM, Inker LA, Coresh J

Abstract

BACKGROUND: Cystatin C level predicts mortality more strongly than serum creatinine level. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other novel renal filtration markers share this advantage in predicting outcomes. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years. PREDICTORS: Serum creatinine-based estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR(CKD-EPI)) and cystatin C, β-trace protein (BTP), and β(2)-microglobulin (B2M) levels. OUTCOMES: Mortality, coronary heart disease, heart failure, and kidney failure. RESULTS: Higher cystatin C and B2M concentrations were associated more strongly with mortality (n = 1,425) than BTP level and all were associated more strongly than eGFR(CKD-EPI) (adjusted HR for the upper 6.7 percentile compared with the lowest quintile: 1.6 [95% CI, 1.3-1.9] for eGFR(CKD-EPI), 2.9 [95% CI, 2.3-3.6] for cystatin C level, 1.9 [95% CI, 1.5-2.4] for BTP level, and 3.0 [95% CI, 2.4-3.8] for B2M level). Similar patterns were observed for coronary heart disease (n = 1,279), heart failure (n = 803), and kidney failure (n = 130). The addition of cystatin C, BTP, and B2M levels to models including eGFR(CKD-EPI) and all covariates, including urinary albumin-creatinine ratio, significantly improved risk prediction for all outcomes (P < 0.001). LIMITATIONS: No direct measurement of GFR. CONCLUSIONS: B2M and, to a lesser extent, BTP levels share cystatin C’s advantage over eGFR(CKD-EPI) in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with decreased kidney function beyond current estimates based on eGFR(CKD-EPI).

PMID: 22305758 [PubMed - as supplied by publisher]

Age and the Associations of Living Donor and Expanded Criteria Donor Kidneys With Kidney Transplant Outcomes.

Am J Kidney Dis. 2012 Feb 3;

Authors: Molnar MZ, Streja E, Kovesdy CP, Shah A, Huang E, Bunnapradist S, Krishnan M, Kopple JD, Kalantar-Zadeh K

Abstract

BACKGROUND: Recent studies show a survival advantage with kidney transplant in elderly patients compared with those on dialysis therapy. STUDY DESIGN: In our present study, we examined and compared the association of expanded criteria donor (ECD) kidney and living kidney donation with the outcome of kidney transplant across different ages, including elderly recipients. SETTING & PARTICIPANTS: Using the Scientific Registry of Transplant Recipients, we identified 145,470 adult kidney transplant patients. Mortality and death-censored transplant failure risks were estimated by Cox proportional regression analyses during follow-up with a median of 3.9 years. PREDICTORS: ECD kidney and living kidney donation and age compared with others. OUTCOMES: Mortality and death-censored transplant failure risk. RESULTS: Patients were aged 45 ± 16 years and included 40% women and 19% patients with diabetes. Compared with transplant recipients 55 to younger than 65 years, the fully adjusted death-censored transplant failure risk was higher in patients 75 years and older (HR, 1.30; 95% CI, 1.09-1.56), 35 to younger than 55 years (HR, 1.13; 95% CI, 1.08-1.17), and 18 to younger than 35 years (HR, 1.64; 95% CI, 1.57-1.71). Compared with non-ECD kidneys, ECD kidneys were significant predictors of mortality in nonelderly patients (18-<35 years: HR, 1.46 [95% CI, 1.19-1.77]; 35-<55 years: HR, 1.23 [95% CI, 1.14-1.32]; and 55-<65 years: HR, 1.26 [95% CI, 1.15-1.38]) and patients 65 to younger than 70 years (HR, 1.20; 95% CI, 1.05-1.36), but not in other groups of elderly patients (HRs of 1.12 [95% CI, 0.93-1.36] for 70-<75 years and 1.04 [95% CI, 0.74-1.47] for ≥75 years). Similar results were found for risk of transplant loss. Compared with deceased donor kidneys, a living donor kidney was associated with better survival in all age groups and lower transplant loss risk in patients younger than 70 years. LIMITATIONS: Unmeasured confounders cannot be adjusted for. CONCLUSIONS: For deceased donors, ECD kidneys are not associated with increased mortality or transplant failure in recipients older than 70 years. For all types of donors, the persistent association between living donor kidneys and lower all-cause mortality across all ages suggests that, if possible, elderly patients gain longevity from living donor kidney transplant.

PMID: 22305759 [PubMed - as supplied by publisher]

Trajectories of Kidney Function Decline in the 2 Years Before Initiation of Long-term Dialysis.

Am J Kidney Dis. 2012 Feb 3;

Authors: O’Hare AM, Batten A, Burrows NR, Pavkov ME, Taylor L, Gupta I, Todd-Stenberg J, Maynard C, Rodriguez RA, Murtagh FE, Larson EB, Williams DE

Abstract

BACKGROUND: Little is known about patterns of kidney function decline leading up to the initiation of long-term dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 5,606 Veterans Affairs patients who initiated long-term dialysis in 2001-2003. PREDICTOR: Trajectory of estimated glomerular filtration rate (eGFR) during the 2-year period before initiation of long-term dialysis. OUTCOMES & MEASUREMENTS: Patient characteristics and care practices before and at the time of dialysis initiation and survival after initiation. RESULTS: We identified 4 distinct trajectories of eGFR during the 2-year period before dialysis initiation: 62.8% of patients had persistently low level of eGFR <30 mL/min/1.73 m(2) (mean eGFR slope, 7.7 ± 4.7 [SD] mL/min/1.73 m(2) per year), 24.6% had progressive loss of eGFR from levels of approximately 30-59 ml/min/1.73 m(2) (mean eGFR slope, 16.3 ± 7.6 mL/min/1.73 m(2) per year), 9.5% had accelerated loss of eGFR from levels >60 mL/min/1.73 m(2) (mean eGFR slope, 32.3 ± 13.4 mL/min/1.73 m(2) per year), and 3.1% experienced catastrophic loss of eGFR from levels >60 mL/min/1.73 m(2) within 6 months or less. Patients with steeper eGFR trajectories were more likely to have been hospitalized and have an inpatient diagnosis of acute kidney injury. They were less likely to have received recommended predialysis care and had a higher risk of death in the first year after dialysis initiation. CONCLUSIONS: There is substantial heterogeneity in patterns of kidney function loss leading up to the initiation of long-term dialysis perhaps calling for a more flexible approach toward preparing for end-stage renal disease.

PMID: 22305760 [PubMed - as supplied by publisher]

Differences Between Dialysis Modality Selection and Initiation.

Am J Kidney Dis. 2012 Feb 2;

Authors: Liebman SE, Bushinsky DA, Dolan JG, Veazie P

Abstract

BACKGROUND: Although dialysis modality education is associated with higher rates of peritoneal dialysis (PD) use, some patients start hemodialysis (HD) therapy despite initially selecting PD as their modality of choice. This study seeks to identify predictors of this discrepancy. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 217 patients who received dialysis modality education at the University of Rochester between January 2004 and September 2009 and subsequently started dialysis therapy. PREDICTORS: Demographic (age, race, sex, and timing of education), social (education, income, insurance, marital, employment, and smoking status), and clinical data (estimated glomerular filtration rate, cause of end-stage renal disease [ESRD], number of comorbid conditions, and number of nephrology visits). OUTCOME: HD use at initiation and day 91 of dialysis therapy in patients initially selecting PD. RESULTS: Of 217 patients receiving education and starting dialysis therapy, at the time of education, 124 chose PD, 52 were undecided, and 41 chose HD. Modality distribution at the time of dialysis therapy initiation was 150 with HD and 67 with PD. Of 124 patients who chose PD at the time of education, 59 started dialysis therapy with PD and 65 started with HD. On day 91, a total of 60 patients were on PD therapy and 55 were on HD therapy. Nine patients had either died, undergone transplant, or not yet reached 91 days of dialysis therapy. On multivariable analysis, nonglomerular cause of ESRD, age older than 75 years, and not being employed predicted starting with HD therapy, whereas age older than 75 years, nonwhite race, and nonglomerular cause of ESRD predicted HD use at day 91. LIMITATIONS: Single-center observational study. CONCLUSIONS: This study shows that patients choosing PD after dialysis education may not start with this modality and identifies several predictors of this mismatch. Further investigation into predictors of this discrepancy and strategies promoting a PD start in patients selecting this modality are warranted.

PMID: 22305859 [PubMed - as supplied by publisher]

Nesiritide ASCENDs the Ranks of Unproven Treatments for Acute Heart Failure.

Am J Kidney Dis. 2012 Feb 2;

Authors: Kociol RD, Konstam MA

PMID: 22305860 [PubMed - as supplied by publisher]

The role of leptin and its short-form receptor in inflammation in db/db mice infused with peritoneal dialysis fluid.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Leung JC, Chan LY, Lam MF, Tang SC, Chow CW, Lim AI, Lai KN

Abstract

BACKGROUND: In peritoneal dialysis (PD), the peritoneal membrane exhibits structural and functional changes following continuous exposure to the non-physiological peritoneal dialysis fluid (PDF). In this study, we examined the effect of PDF on peritoneal adipose tissue in a diabetic milieu.METHODS: Six-week-old db/db mice and their non-diabetic littermates (db/m) were subjected to uninephrectomy. All animals then received intra-abdominal infusion of lactated Ringer’s solution (Ringer) or 1.5% glucose-containing PDF (Dianeal) twice daily. Mice were sacrificed 4 weeks later. Parietal and visceral adipose tissues were harvested for examining gene and protein expression of adiponectin, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, tumor necrosis factor alpha (TNF-α), transforming growth factor beta and interleukin 6 (IL-6). Expression of TNF-α and F4/80+ macrophage accumulation in adipose tissues was assessed by immunohistochemical staining. Modulation of leptin synthesis and leptin receptors expression and the relevant signaling pathways were also determined by quantitative reverse transcription-polymerase chain reaction, immunoblotting or enzyme-linked immunosorbent assay.RESULTS: Compared to Ringer infusion, Dianeal infusion significantly increased serum leptin but decreased adiponectin in db/db mice. Increased expression of leptin, TNF-α and IL-6 was observed in visceral but not in parietal adipose tissue. Dianeal infusion also increased F4/80+ macrophage accumulation and enhanced the expression of pro-inflammatory cytokines including IL-6 and TNF-α in the visceral adipose tissue. Compared to db/m mice, infusion with Dianeal exhibited a more deleterious effect on db/db mice, characterized by an upregulation of short-form leptin receptor ObRa and activation of the mitogen-activated protein kinase signaling pathway.CONCLUSION: In conclusion, PD-induced hyperleptinemia amplifies the inflammatory response of adipose tissue through short-form leptin receptor when the long-form isotype is defective.

PMID: 22287654 [PubMed - as supplied by publisher]

Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-α

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Aoshima Y, Mizobuchi M, Ogata H, Kumata C, Nakazawa A, Kondo F, Ono N, Koiwa F, Kinugasa E, Akizawa T

Abstract

BACKGROUND: Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D(3) analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α.METHODS: Human VSMCs were treated with either vehicle, maxacalcitol (10(-9) to 10(-7) M), or calcitriol (10(-9) to 10(-7) M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed.RESULTS: Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol.CONCLUSIONS: Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification.

PMID: 22287655 [PubMed - as supplied by publisher]

Progression to hypertension in non-hypertensive children following renal transplantation.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Sinha MD, Gilg JA, Kerecuk L, Reid CJ,

Abstract

BACKGROUND: The aim of this study was to evaluate in non-hypertensive children following renal transplantation (TX) the rates and determinants of transition to hypertension.METHODS: Retrospective case note review of all current paediatric kidney transplant patients in the UK. At baseline (6 months following TX), all included subjects were non-hypertensive with systolic and/or diastolic clinic blood pressure (BP) ≤95th percentile while on no anti-hypertensive therapy. We assessed progression from optimal (systolic and/or diastolic clinic BP <50th percentile), normal (systolic and/or diastolic clinic BP ≥50th but <90th percentile) and pre-hypertension (systolic and/or diastolic clinic BP 90th-95th percentile) to hypertension (systolic and/or diastolic clinic BP >95th percentile). If systolic and diastolic BP levels belonged to different categories, the higher of the two levels were used for categorization.RESULTS: At baseline, 146 of 524 (27.9%) children (106 male) median [inter-quartile range (IQR)] age 7.8 years (4.8, 11.8) were non-hypertensive and not on any anti-hypertensive therapy; there were 34 patients (23.2%) with optimal BP, 90 (61.6%) with normal BP and 22 (15.1%) with pre-hypertension. They were followed up for a median of 2.0 (1.0, 4.0) years post-TX. At the end of follow-up, BP was optimal in 37 patients (25.3%), normal in 35 (24.0%), high normal in 2 (1.4%) and 72 (49.3%) had progressed to hypertension. The Kaplan-Meier estimated time at which 50% of patients developed hypertension was 2.0 years for the pre-hypertension and 3.0 years in the normal BP group as opposed to 40% risk at 7-year post-TX in the optimal group (P = 0.001 between the three groups). The differences between BP groups remained significant after adjustment for all risk factors on multivariate analysis.CONCLUSIONS: Just over 49% of our initially non-hypertensive patients progressed to hypertension following TX. BP needs careful monitoring post-TX and ideally should be maintained in the ‘normal’ and ‘optimal’ range.

PMID: 22287656 [PubMed - as supplied by publisher]

The UNOS ‘preferential allocation’ concept proposal for the allocation of deceased donor kidney transplants: implications for patients with diabetes.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Xu S, Williams ME, Pavlakis M, Breu AC

PMID: 22287657 [PubMed - as supplied by publisher]

Liver cell transplantation in severe infantile oxalosis–a potential bridging procedure to orthotopic liver transplantation?

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Beck BB, Habbig S, Dittrich K, Stippel D, Kaul I, Koerber F, Goebel H, Salido EC, Kemper M, Meyburg J, Hoppe B

Abstract

BACKGROUND: The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely.METHODS: We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure.RESULTS: Pox decreased from 104.3 ± 8.4 prior to 70.0 ± 15.0 μmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P < 0.001) comparing mean levels prior to (103.8 μmol/L) and after Day 14 of LCT until LKTx (77.3 μmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient’s clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction.CONCLUSIONS: With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

PMID: 22287658 [PubMed - as supplied by publisher]

In vitro reconstitution of human kidney structures for renal cell therapy.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Guimaraes-Souza NK, Yamaleyeva LM, Aboushwareb T, Atala A, Yoo JJ

Abstract

BACKGROUND: Recent advances in cell therapies have provided potential opportunities for the treatment of chronic kidney diseases (CKDs). We investigated whether human kidney structures could be preformed in vitro for subsequent implantation in vivo to maximize tissue-forming efficiency.METHODS: Human renal cells were isolated from unused donor kidneys. Human renal cells were cultured and expanded. Migration was analyzed using growth factors. To form structures, cells were placed in a three-dimensional culture system. Cells were characterized by immunofluorescence, western blots and fluorescence-activated cell sorting using renal cell-specific markers for podocin, proximal and distal tubules and collecting ducts. An albumin uptake assay was used to analyze function. Three-dimensional cultures were implanted into athymic rat kidneys to evaluate survival.RESULTS: Human renal cells were effectively expanded in culture and retained their phenotype, migration ability and albumin uptake functions. Human renal cell in three-dimensional culture-formed tubules, which stained positively for proximal, distal tubule and collecting duct markers, and this was confirmed by western blot. Polarity of the tubular cells was determined by the presence of E-cadherin, N-cadherin and Na-K ATPase. Colocalization of labeled albumin and proximal tubule markers proved functionality and specificity of the newly formed tubules. An in vivo study showed that cells survived in the kidney for up to 6 weeks.CONCLUSIONS: These findings demonstrate that human renal cell grown in three-dimensional culture are able to generate kidney structures in vitro. This system may ultimately be developed into an efficient cell-based therapy for patients with CKD.

PMID: 22287659 [PubMed - as supplied by publisher]

Renal transplantation in the elderly.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Basic-Jukic N, Kes P

PMID: 22287660 [PubMed - as supplied by publisher]

Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples.

Nephrol Dial Transplant. 2012 Jan 28;

Authors: Goek ON, Köttgen A, Hoogeveen RC, Ballantyne CM, Coresh J, Astor BC

Abstract

BACKGROUND: Circulating lipoproteins and their protein constituents, apolipoproteins, are risk factors for chronic kidney disease (CKD). The associations between apolipoprotein A1, apolipoprotein B and their ratio with glomerular filtration rate estimated from the new CKD Epidemiology Collaboration (CKD-EPI) equation (eGFR) are not well studied in the general population.METHODS: Associations between apolipoprotein A1, B and their ratio with the outcomes of eGFR, CKD (eGFR <60 mL/min/1.73m(2)) and albuminuria were examined in the Atherosclerosis Risk in Communities study (ARIC, n = 10 292, 1996-98) and the Third National Health and Nutrition Examination Survey (NHANES III, n = 7023, 1988-91). Cross-sectional multivariable-adjusted analyses were performed using linear and logistic regression. Prospective analyses related baseline apolipoprotein levels to subsequent CKD incidence over 10 years using the ARIC Carotid MRI follow-up cohort (n = 1659).RESULTS: Higher apolipoprotein A1 quartiles were associated with a lower prevalence of CKD [Q4 versus Q1: odds ratio (OR) 0.73, P-trend = 0.02 in ARIC; Q4 versus Q1: OR 0.53, P-trend < 0.01 in NHANES III] as well as with higher eGFR (P-trend < 0.01 in ARIC and NHANES III). No consistent significant associations were found for apolipoprotein B in either study. The apolipoprotein B/A1 ratio was significantly associated with eGFR across quartiles in both studies (P-trend < 0.01) and with CKD in ARIC (Q4 versus Q1: OR 1.23, P-trend = 0.01). Prospectively, there were trends for the association of apolipoproteins with incident CKD [Q4 versus Q1: incidence rate ratio (IRR) = 0.68 for apolipoprotein A1, P-trend = 0.1; Q4 versus Q1: IRR = 1.35 for apolipoprotein B, P-trend = 0.2]. Associations were not systematically stronger when comparing traditional lipids (total cholesterol, low-density lipoprotein or high-density lipoprotein) to apolipoproteins.CONCLUSIONS: Higher serum apolipoprotein A1 was associated with lower prevalence of CKD and higher eGFR estimated by the CKD-EPI equation in two large multiethnic population-based samples. While apolipoprotein B showed no consistent associations, a higher apolipoprotein B/A1 ratio was significantly associated with lower eGFR in both studies. The direction and magnitude of the longitudinal associations between apolipoproteins and CKD incidence were overall similar to those observed cross-sectionally. No consistent differences became apparent between traditional lipids and apolipoproteins.

PMID: 22287661 [PubMed - as supplied by publisher]

Report from the editorial offices.

Nephrol Dial Transplant. 2012 Jan;27(1):1-3

Authors: Zoccali C

PMID: 22287697 [PubMed - in process]

Editorial.

Nephrol Dial Transplant. 2012 Jan;27(1):4-5

Authors:

PMID: 22287698 [PubMed - in process]

Haematuria: the forgotten CKD factor?

Nephrol Dial Transplant. 2012 Jan;27(1):28-34

Authors: Moreno JA, Martín-Cleary C, Gutiérrez E, Rubio-Navarro A, Ortiz A, Praga M, Egido J

Abstract

Haematuria is a frequent manifestation of glomerular disease. However, nephrologists devote more attention to the monitoring and therapeutic targeting of another key manifestation of glomerular injury, proteinuria. Recent reports have propelled haematuria to the forefront of clinical nephrology. Thus, glomerular macroscopic haematuria is associated with the development of acute kidney injury (AKI) with predominant tubular cell damage and there is increasing evidence for the negative impact of glomerular haematuria-associated AKI on long-term renal function outcome both in the context of IgA nephropathy and in anticoagulated patients. In addition, an epidemiological association between isolated microscopic haematuria in young adults and long-term incidence of end-stage renal disease has been described. Finally, a clearer understanding of how haematuria may cause tubular injury is emerging through detailed histological assessment of human biopsies and experimental models of haemoglobin-mediated nephrotoxicity.

PMID: 22287699 [PubMed - in process]

Medical management of hepatorenal syndrome.

Nephrol Dial Transplant. 2012 Jan;27(1):34-41

Authors: Davenport A, Ahmad J, Al-Khafaji A, Kellum JA, Genyk YS, Nadim MK

Abstract

Hepatorenal syndrome (HRS) is defined as the occurrence of renal dysfunction in a patient with end-stage liver cirrhosis in the absence of another identifiable cause of renal failure. The prognosis of HRS remains poor, with a median survival without liver transplantation of <6 months. However, understanding the pathogenesis of HRS has led to the introduction of treatments designed to increase renal perfusion and mean arterial blood pressure using vasopressors and albumin, which has led to improvement in renal function in ∼50% of patients.

PMID: 22287700 [PubMed - in process]

Outcome of the living kidney donor.

Nephrol Dial Transplant. 2012 Jan;27(1):41-50

Authors: Delanaye P, Weekers L, Dubois BE, Cavalier E, Detry O, Squifflet JP, Krzesinski JM

Abstract

Renal transplantation from living kidney donors is still relatively marginal in most of the European countries. However, this source of kidney grafts may help to overcome in part the organ donor shortage of cadaveric donors. The living donor strategy implies correct and objective information about donation risks and completely free acceptance of the living candidate of the donation. In this paper, we reviewed the consequences of kidney donation on the living donor health, considering very short term (linked to the surgery), short term (effect of nephrectomy on glomerular filtration rate) and long term (risk of mortality, chronic kidney disease, proteinuria and hypertension) consequences of kidney donation.

PMID: 22287701 [PubMed - in process]

Uraemic toxins versus volume and water as the major factor that matters with dialysis.

Nephrol Dial Transplant. 2012 Jan;27(1):58-62

Authors: Covic A, Voroneanu L, Locatelli F

PMID: 22287702 [PubMed - in process]

The ultimate salt war? Uraemic toxins are all that count in dialysis patients.

Nephrol Dial Transplant. 2012 Jan;27(1):62-6

Authors: Vanholder R

PMID: 22287703 [PubMed - in process]

The ERA-EDTA Working Group on inherited kidney disorders.

Nephrol Dial Transplant. 2012 Jan;27(1):67-9

Authors: Devuyst O, Antignac C, Bindels RJ, Chauveau D, Emma F, Gansevoort R, Maxwell PH, Ong AC, Remuzzi G, Ronco P, Schaefer F

PMID: 22287704 [PubMed - in process]

Drug-induced erythropoiesis and outcome: should we give up the haemoglobin target approach and return to the ratio between erythropoiesis-stimulating agents and haemoglobin?

Nephrol Dial Transplant. 2012 Jan;27(1):454

Authors: Canavese C, Salomone M, Stratta P

PMID: 22287705 [PubMed - in process]

We sincerely thank all our subject and section editors for their hard work over the past year.

Nephrol Dial Transplant. 2012 Jan;27(1):457-68

Authors:

PMID: 22287706 [PubMed - in process]

Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients.

Nephrol Dial Transplant. 2012 Jan 30;

Authors: Agarwal R

Abstract

BACKGROUND: The prevalence, determinants and prognosis of pulmonary hypertension among long-term hemodialysis patients in the USA are poorly understood.METHODS: A cross-sectional survey of prevalence and determinants of pulmonary hypertension was performed, followed by longitudinal follow-up for all-cause mortality. Pulmonary hypertension was defined as an estimated systolic pulmonary artery pressure of >35 mmHg using echocardiograms performed within an hour after the end of dialysis.RESULTS: Prevalent in 110/288 patients (38%), the independent determinants of pulmonary hypertension were the following: left atrial diameter (odds ratio 10.1 per cm/m(2), P < 0.0001), urea reduction ratio (odds ratio 0.94 per %, P < 0.01) and vitamin D receptor activator use (odds ratio 0.41 for users, P < 0.01). Over a median follow-up of 2.15 years, 97 (34%) patients died yielding a crude mortality rate (CMR) of 114.2 per 1000 patient-years. Of these, 58 deaths occurred among 110 patients with pulmonary hypertension (53%, CMR 168.9/1000 patient-years) and 39 among 178 without pulmonary hypertension (22%, CMR 52.5/1000 patient-years) [unadjusted hazard ratio (HR) for death 2.12 (95% confidence interval 1.41-3.19), P < 0.001]. After multivariate adjustment, pulmonary hypertension remained an independent predictor for all-cause mortality [HR 2.17 (95% confidence interval 1.31-3.61), P < 0.01].CONCLUSIONS: Among hemodialysis patients, pulmonary hypertension is common and is strongly associated with an enlarged left atrium and poor long-term survival. Reducing left atrial size such as through volume control may be an attractive target to improve pulmonary hypertension. Improving pulmonary hypertension in this group of patients may improve the dismal outcomes.

PMID: 22290987 [PubMed - as supplied by publisher]

Acute dialysis risk in living kidney donors.

Nephrol Dial Transplant. 2012 Jan 30;

Authors: Lam N, Huang A, Feldman LS, Gill JS, Karpinski M, Kim J, Klarenbach SW, Knoll GA, Lentine KL, Nguan CY, Parikh CR, Prasad GV, Treleaven DJ, Young A, Garg AX,

Abstract

BACKGROUND: Reduced kidney function confers a higher risk of acute kidney injury at the time of an inciting event, such as sepsis. Whether the same is true in those with reduced renal mass from living kidney donation is unknown.METHODS: We conducted a population-based matched cohort study of all living kidney donors in the province of Ontario, Canada who underwent donor nephrectomy from 1992 to 2009. We manually reviewed the medical records of these living kidney donors and linked this information to provincial health care databases. Non-donors were selected from the healthiest segment of the general population.RESULTS: There were 2027 donors and 20 270 matched non-donors. The median age was 43 years (interquartile range 34-50) and individuals were followed for a median of 6.6 years (maximum 17.7 years). The primary outcome was acute dialysis during any hospital stay. Reasons for hospitalization included infectious diseases, cardiovascular diseases and hematological malignancies. Only one donor received acute dialysis in follow-up (6.5 events per 100 000 person-years), a rate which was statistically no different than 14 non-donors (9.4 events per 100 000 person-years).CONCLUSIONS: These results are reassuring for the practice of living kidney donation. Longer follow-up of this and other donor cohorts will provide more precise estimates about this risk.

PMID: 22290988 [PubMed - as supplied by publisher]

Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice.

Nephrol Dial Transplant. 2012 Jan 30;

Authors: Stylianou K, Petrakis I, Mavroeidi V, Stratakis S, Kokologiannakis G, Lioudaki E, Liotsi C, Kroustalakis N, Vardaki E, Stratigis S, Perakis K, Kyriazis J, Nakopoulou L, Daphnis E

Abstract

BACKGROUND: In the normal kidney, rapamycin is considered to be non-nephrotoxic. In the present study, we investigated whether rapamycin is indeed non-nephrotoxic by examining the ultrastructural and molecular alterations of podocytes in healthy mice.METHODS: Balb/c mice were given three different intraperitoneal doses of rapamycin for 1 week (dose model)-low-dose group: 1 mg/kg/day, intermediate-dose (ID) group: 1.5 mg/kg/day and high-dose (HD) group: 3 mg/kg/day; four mice in each group. An ID of rapamycin was also given for three different periods (time model): 1, 4 and 8 weeks; four mice were in each group. Mice treated with dimethyl sulphoxide served as controls. Body weight was measured weekly. Renal function was assessed by serum creatinine at the time of sacrifice. For estimation of albuminuria, 24-h urine collections were performed before treatment and weekly thereafter. Glomerular content of nephrin, podocin, Akt and Ser473-phospho-Akt was estimated by western blot and immunofluorescence. Nephrin and podocin messenger RNA (mRNA) were measured by real-time polymerase chain reaction. Mean podocyte foot process width (FPW) was measured by electron microscopy.RESULTS: Urine albumin levels increased in the HD and 4-week groups. Renal function was modestly deteriorated in the HD group. The mean FPW increased in a dose-dependant manner at Week 1, further deteriorated at Week 4 and finally improved at Week 8. Nephrin and podocin mRNA levels showed a significant decrease at Week 1 and were restored at Week 4 and 8. Nephrin and podocin protein levels were reduced at Week 4 and recovered at Week 8. Ser473-phospho-Akt significantly increased in all rapamycin-treated groups.CONCLUSIONS: Rapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period.

PMID: 22290989 [PubMed - as supplied by publisher]

Ultrasound renal resistive index is not an organ-specific predictor of allograft outcome.

Nephrol Dial Transplant. 2012 Jan 30;

Authors: Seiler S, Colbus SM, Lucisano G, Rogacev KS, Gerhart MK, Ziegler M, Fliser D, Heine GH

Abstract

BACKGROUND: Ultrasound-measured renal resistive index (RRI) has been suggested to predict allograft survival in renal transplant recipients. Based on experimental and clinical data, we objected to the theory that RRI specifically mirrors allograft characteristics. Instead, we hypothesized that RRI rather represents a marker of systemic vascular damage than an organ-specific marker. In order to refute this hypothesis, RRI should override the resistive index measured in other abdominal parenchymatous organs-such as the spleen-as predictor of allograft outcome. We therefore set out to simultaneously measure renal and splenic ultrasound resistive index in kidney allograft recipients.METHODS: Eighty-seven stable transplant recipients were recruited. We measured RRI, splenic resistive index (SRI) and an established marker of systemic vascular damage, namely common carotid intima-media thickness (IMT). During a follow-up of 4.9 ± 0.5 years, the occurrence of the combined primary end point, defined as a decrease of ≥50% in estimated glomerular filtration rate (eGFR), need for dialysis treatment or death, was recorded.RESULTS: At baseline, both RRI and SRI correlated with common carotid IMT [RRI: r = 0.203 (P = 0.006); SRI: r = 0.315 (P < 0.001)], but not with allograft-specific markers such as eGFR or proteinuria. Elevated RRI was a weak non-significant predictor of the combined primary end point. Notably, RRI did not surpass SRI as outcome predictor. When analysing individual components of the combined primary end point separately, elevated RRI failed to predict strictly renal events (decrease of ≥50% in eGFR/need for dialysis treatment), while it predicted total mortality.CONCLUSIONS: Our findings support the notion that RRI is not a specific indicator of allograft damage. Similar to SRI, RRI is rather associated with systemic vascular damage markers and mortality.

PMID: 22290990 [PubMed - as supplied by publisher]

One dose of cyclosporine A is protective at initiation of folic acid-induced acute kidney injury in mice.

Nephrol Dial Transplant. 2012 Jan 31;

Authors: Wen X, Peng Z, Li Y, Wang H, Bishop JV, Chedwick LR, Singbartl K, Kellum JA

Abstract

BACKGROUND: In most patients, acute kidney injury (AKI) represents the combined effects of ischemic, toxic and inflammatory insults. No effective pharmacologic interventions have been developed to prevent AKI or to improve outcomes to date. Cyclosporine A (CsA) is a calcineurin inhibitor that mediates T-cell receptor signaling, suppresses inflammatory cytokine expression and inhibits leukocyte migration. It is also a potent inhibitor of mitochondrial permeability, protecting cells from death. These properties make it a potentially valuable drug to prevent or treat AKI. It does, however, carry a significant risk of nephrotoxicity, especially with chronic use. By contrast, a single dose of CsA may be protective while limiting the risk of nephrotoxicity.METHODS: We conducted a controlled animal experiment in male CD-1 mice. Specifically, mice were subjected to folic acid (FA)-induced AKI and then randomly assigned to sham operation or one of three dosage of CsA treatment groups.RESULTS: Intraperitoneal injection of FA consistently induced AKI. Serum interleukin (IL)-6 and urinary neutrophil gelatinase-associated lipocalin (NGAL) rose 1 day after FA injection. Compared to sham treatment, one dose (1 and 5 mg/kg body weight) of CsA significantly reduced kidney tubular cell apoptosis, serum creatinine, blood urea, serum IL-6 and urinary NGAL 2 days after FA injection. It was also shown to block the inflammatory mediator tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) expression, nuclear factor kappa-B (NFκB) activation, inflammatory cell infiltration and interstitial fibrosis 14 days after treatment in a dose-dependent fashion. By contrast, a dose of 10 mg/kg body weight CsA resulted in nephrotoxicity in the setting of FA-induced AKI.CONCLUSIONS: A single dose of CsA, currently used for organ transplant, significantly protects mice from FA-induced AKI, presumably through inhibition of cell death, inflammatory reaction, interstitial cell infiltration and fibrosis. The protective effects have the potential to open a completely new line of investigation in the prevention and treatment of AKI.

PMID: 22294776 [PubMed - as supplied by publisher]

Proof-of-principle study to detect metabolic changes in peritoneal dialysis effluent in patients who develop encapsulating peritoneal sclerosis.

Nephrol Dial Transplant. 2012 Jan 31;

Authors: Dunn WB, Summers A, Brown M, Goodacre R, Lambie M, Johnson T, Wilkie M, Davies S, Topley N, Brenchley P

Abstract

BACKGROUND: Prolonged peritoneal dialysis (PD) therapy can result in the development of encapsulating peritoneal sclerosis (EPS), characterized by extensive sclerosis of the peritoneum with bowel adhesions often causing obstruction.METHODS: As a proof-of-principle study, holistic profiling of endogenous metabolites has been applied in a prospective collection of PD effluent collected in multiple UK renal centres over 6 years in order to investigate metabolic differences in PD effluent between PD therapy patients who later developed clinically defined EPS (n = 11) and controls, who were matched for PD vintage, age and gender (n = 11).RESULTS: ‘Fit-for-purpose’ analytical methods employing gas chromatography-mass spectrometry (MS), direct injection MS and quality control samples were developed and validated. These methods were applied in a proof-of-principle study to define metabolic differences in PD effluent related to subsequent development of EPS. Changes in amino acids, amines and derivatives, short-chain fatty acids and derivatives and sugars were observed prior to EPS developing, and changes in the metabolomic profiles could be detected.CONCLUSION: There is potential for applying metabolic profiles to identify patients at risk of developing EPS although long-term prospective studies with larger patient cohorts are required.

PMID: 22294777 [PubMed - as supplied by publisher]

The role of myocardial scintigraphy in the assessment of cardiovascular risk in patients with end-stage chronic kidney disease on the waiting list for renal transplantation.

Nephrol Dial Transplant. 2012 Feb 1;

Authors: Galvão De Lima JJ, Wolff Gowdak LH, Jota de Paula F, Franchini Ramires JA, Bortolotto LA

Abstract

BACKGROUND: The usefulness of stress myocardial perfusion scintigraphy for cardiovascular (CV) risk stratification in chronic kidney disease remains controversial. We tested the hypothesis that different clinical risk profiles influence the test.METHODS: We assessed the prognostic value of myocardial scintigraphy in 892 consecutive renal transplant candidates classified into four risk groups: very high (aged ≥50 years, diabetes and CV disease), high (two factors), intermediate (one factor) and low (no factor).RESULTS: The incidence of CV events and death was 20 and 18%, respectively (median follow-up = 22 months). Altered stress testing was associated with an increased probability of cardiovascular events only in intermediate-risk (one risk factor) patients [30.3 versus 10%, hazard ratio (HR) = 2.37, confidence interval (CI) 1.69-3.33, P < 0.0001]. Low-risk patients did well regardless of scan results. In patients with two or three risk factors, an altered stress test did not add to the already increased CV risk. Myocardial scintigraphy was related to overall mortality only in intermediate-risk patients (HR = 2.8, CI 1.5-5.1, P = 0.007).CONCLUSIONS: CV risk stratification based on myocardial stress testing is useful only in patients with just one risk factor. Screening may avoid unnecessary testing in 60% of patients, help stratifying for risk of events and provide an explanation for the inconsistent performance of myocardial scintigraphy.

PMID: 22302207 [PubMed - as supplied by publisher]

Combination therapy with an angiotensin II receptor blocker and an HMG-CoA reductase inhibitor in experimental subtotal nephrectomy.

Nephrol Dial Transplant. 2012 Feb 1;

Authors: Alvarez-Prats A, Hernández-Perera O, Díaz-Herrera P, Ucero AC, Anabitarte-Prieto A, Losada-Cabrera A, Ortiz A, Rodríguez-Pérez JC

Abstract

BACKGROUND: Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease.METHODS: Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys.RESULTS: In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries.CONCLUSIONS: In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.

PMID: 22302208 [PubMed - as supplied by publisher]

The new era of APOL1-associated glomerulosclerosis.

Nephrol Dial Transplant. 2012 Feb 2;

Authors: Freedman BI, Langefeld CD

PMID: 22302261 [PubMed - as supplied by publisher]

Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes.

Arterioscler Thromb Vasc Biol. 2012 Feb 2;

Authors: Nogueira JP, Maraninchi M, Béliard S, Padilla N, Duvillard L, Mancini J, Nicolay A, Xiao C, Vialettes B, Lewis GF, Valéro R

Abstract

OBJECTIVE: Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes. METHODS AND RESULTS: We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL. CONCLUSIONS: This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis.Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique identifier: NCT00950209.

PMID: 22308041 [PubMed - as supplied by publisher]

Intravascular Optical Coherence Tomography Detection of Atherosclerosis and Inflammation in Murine Aorta.

Arterioscler Thromb Vasc Biol. 2012 Feb 2;

Authors: Tahara S, Morooka T, Wang Z, Bezerra HG, Rollins AM, Simon DI, Costa MA

Abstract

OBJECTIVE: The goal of this study was to evaluate the feasibility of imaging the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice for the detection of atherosclerosis and macrophages using optical coherence tomography (OCT) compared with histology. METHODS AND RESULTS: Atherosclerosis was induced by high-fat diet in 7-week-old ApoE(-/-) mice for 10 (n=7) and 22 (n=7) weeks. Nine-week-old ApoE(-/-) mice (n=7) fed a standard chow diet were used as controls. OCT images of a 10-mm descending aorta in situ were performed in 4 mice for each, and plaque and macrophages were determined at 0.5-mm intervals. Automated detection and quantification of macrophages were performed independently using a customized algorithm. Coregistered histological cross-sections were stained with hematoxylin-eosin, Mac-3, and von Kossa. Three mice in each group had en face OCT imaging to detect macrophages, which were compared with lipid-positive area with Sudan IV. OCT images were successfully acquired in all mice. OCT and histology were able to discriminate macrophages and plaque among the 3 groups and showed excellent correlation for (1) visual detection of plaque (r=0.98) and macrophages (r=0.93), (2) automated detection and quantification of macrophages by OCT versus Mac-3-positive area (r=0.92), and (3) en face OCT detection of macrophages versus Sudan IV-positive area (r=0.92). CONCLUSIONS: Murine intraaortic OCT is feasible and shows excellent correlation with histology for detection of atherosclerotic plaque and macrophages.

PMID: 22308042 [PubMed - as supplied by publisher]

In Vivo Targeting of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles.

Arterioscler Thromb Vasc Biol. 2012 Feb 2;

Authors: Maiseyeu A, Badgeley MA, Kampfrath T, Mihai G, Deiuliis JA, Liu C, Sun Q, Parthasarathy S, Simon DI, Croce K, Rajagopalan S

Abstract

OBJECTIVE: Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extra cellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes. METHODS AND RESULTS: Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice were. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice and differentiated to macrophages and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14, and conditioned media was collected and used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which were abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed aMrp-NP presence in Ly-6G(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals. CONCLUSIONS: Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.

PMID: 22308043 [PubMed - as supplied by publisher]

Sphingosine-1-Phosphate Receptor 3 Promotes Neointimal Hyperplasia in Mouse Iliac-Femoral Arteries.

Arterioscler Thromb Vasc Biol. 2012 Feb 2;

Authors: Shimizu T, De Wispelaere A, Winkler M, D’Souza T, Caylor J, Chen L, Dastvan F, Deou J, Cho A, Larena-Avellaneda A, Reidy M, Daum G

Abstract

OBJECTIVE: The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia. METHODS AND RESULTS: A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries.T Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more. CONCLUSIONS: In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.

PMID: 22308044 [PubMed - as supplied by publisher]

Tension-Free Vaginal Tape for the Treatment of Urodynamic Stress Incontinence: Efficacy and Adverse Effects at 10-Year Follow-Up.

Eur Urol. 2012 Jan 28;

Authors: Serati M, Ghezzi F, Cattoni E, Braga A, Siesto G, Torella M, Cromi A, Vitobello D, Salvatore S

Abstract

BACKGROUND: One of the most effective and popular current procedures for the surgical treatment of stress urinary incontinence (SUI) is tension-free midurethral slings. OBJECTIVE: To evaluate the outcomes of women with retropubic tension-free vaginal tape (TVT) for urodynamic stress incontinence (USI) after 10-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective observational study. Consecutive women with proven USI were treated with TVT. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded. INTERVENTION: Standard retropubic TVT. MEASUREMENTS: Patients underwent preoperative clinical and urodynamic evaluations. During follow-up examinations, women were assessed for subjective satisfaction and objective cure rates. Multivariable analyses were performed to investigate outcomes. RESULTS AND LIMITATIONS: A total of 63 women were included. After 10 yr, 5 patients (8%) were lost or no longer evaluable. The 10-yr subjective, objective, and urodynamic cure rates were 89.7%, 93.1%, and 91.4%, respectively. These rates were stable across the whole study period (p>0.99). De novo overactive bladder was reported by 30.1% and 18.9% of patients at 3-mo and 10-yr follow-up, respectively (p for trend = 0.19). A total of 84.2% of women with detrusor overactivity received antimuscarinic drugs, but 43.8% were nonresponders 12 wk later. At multivariable analysis, maximum detrusor pressure during the filling phase >9cm H(2)O (hazard ratio [HR]: 16.2; p=0.01) and maximum detrusor pressure during the voiding phase ≤29cm H(2)O (HR: 8.0; p=0.01) were independent predictors for the recurrence of SUI, as well as obesity was for the recurrence of objective SUI (HR: 17.1; p=0.01] and of USI (HR: 8.9; p=0.02), respectively. Intraoperatively, bladder perforation occurred in two cases; no severe bleeding or other complications occurred. CONCLUSIONS: The 10-yr results of this study seem to demonstrate that TVT is a highly effective option for the treatment of female SUI, recording a very high cure rate with low complications after a 10-yr follow-up.

PMID: 22305110 [PubMed - as supplied by publisher]

Spread of OnabotulinumtoxinA After Bladder Injection. Experimental Study Using the Distribution of Cleaved SNAP-25 as the Marker of the Toxin Action.

Eur Urol. 2012 Feb 1;

Authors: Coelho A, Cruz F, Cruz CD, Avelino A

Abstract

BACKGROUND: OnabotulinumtoxinA (Onabot/A) has been used to treat detrusor overactivity disorders. The treatment is based on several injections of toxin throughout the bladder wall. However, injection protocols are not well established among clinicians, varying in dose and dilution. OBJECTIVE: Study the distribution and neurochemistry of cleaved synaptosome-associated protein of 25 kDa (cSNAP-25) after Onabot/A administration in the guinea pig bladder. In addition, we analyzed which factor, dose or volume, contributes more to the diffusion of the toxin. DESIGN, SETTING, AND PARTICIPANTS: Guinea pig bladders were treated with Onabot/A via intramural injection or an instillation. MEASUREMENTS: Bladder cryostat sections were processed for single or dual immunohistochemistry staining with antibodies against cSNAP-25, vesicular acetylcholine transporter, tyrosine hydroxylase, and calcitonin gene-related peptide. Different administration methods and doses were analyzed. Statistical analysis was performed using the chi-square test for colocalization studies after multiple injections and the t test for the evaluation of affected fibers after a single injection. RESULTS AND LIMITATIONS: cSNAP-25 immunoreactive fibers were abundant throughout the bladder tissue in the mucosa and muscular layer. Double labeling showed that parasympathetic fibers are more affected than sympathetic or sensory. A single Onabot/A injection is more effective if diluted in a higher volume. Onabot/A instillation in the bladder does not cleave SNAP-25 protein. CONCLUSIONS: A single Onabot/A injection spreads the neurotoxin activity to the opposite side of the guinea pig bladder. This action is more evident when high saline volumes are used to dissolve Onabot/A. The toxin cleaves the SNAP-25 protein mainly in cholinergic but also in adrenergic and sensory fibers. In contrast with intramural injection, instillation of Onabot/A does not cleave SNAP-25 in nerve fibers.

PMID: 22306320 [PubMed - as supplied by publisher]

Reply From the Authors re: Quoc-Dien Trinh, Jesse Sammon, Maxine Sun, et al. Perioperative Outcomes of Robot-Assisted Radical Prostatectomy Compared With Open Radical Prostatectomy: Results From the Nationwide Inpatient Sample. Eur Urol. In press. DOI:10.1016/j.eururo.2011.12.027 Robotic Prostatectomy: Men Versus Machines-The Machines Are Already Here.

Eur Urol. 2012 Feb 1;

Authors: Trinh QD, Sun M, Sammon J, Menon M, Karakiewicz PI

PMID: 22306321 [PubMed - as supplied by publisher]

Reply from Authors re: Propensity-Score-Matched Comparison of Perioperative Outcomes Between Open and Laparoscopic Nephroureterectomy: A National Series. Eur Urol. In press. DOI:10.1016/j.eururo.2011.12.051.

Eur Urol. 2012 Feb 1;

Authors: Hanna N, Sun M, Bianchi M, Karakiewicz PI

PMID: 22306322 [PubMed - as supplied by publisher]

A Novel Automated Platform for Quantifying the Extent of Skeletal Tumour Involvement in Prostate Cancer Patients Using the Bone Scan Index.

Eur Urol. 2012 Jan 27;

Authors: Ulmert D, Kaboteh R, Fox JJ, Savage C, Evans MJ, Lilja H, Abrahamsson PA, Björk T, Gerdtsson A, Bjartell A, Gjertsson P, Höglund P, Lomsky M, Ohlsson M, Richter J, Sadik M, Morris MJ, Scher HI, Sjöstrand K, Yu A, Suurküla M, Edenbrandt L, Larson SM

Abstract

BACKGROUND: There is little consensus on a standard approach to analysing bone scan images. The Bone Scan Index (BSI) is predictive of survival in patients with progressive prostate cancer (PCa), but the popularity of this metric is hampered by the tedium of the manual calculation. OBJECTIVE: Develop a fully automated method of quantifying the BSI and determining the clinical value of automated BSI measurements beyond conventional clinical and pathologic features. DESIGN, SETTING, AND PARTICIPANTS: We conditioned a computer-assisted diagnosis system identifying metastatic lesions on a bone scan to automatically compute BSI measurements. A training group of 795 bone scans was used in the conditioning process. Independent validation of the method used bone scans obtained ≤3 mo from diagnosis of 384 PCa cases in two large population-based cohorts. An experienced analyser (blinded to case identity, prior BSI, and outcome) scored the BSI measurements twice. We measured prediction of outcome using pretreatment Gleason score, clinical stage, and prostate-specific antigen with models that also incorporated either manual or automated BSI measurements. MEASUREMENTS: The agreement between methods was evaluated using Pearson’s correlation coefficient. Discrimination between prognostic models was assessed using the concordance index (C-index). RESULTS AND LIMITATIONS: Manual and automated BSI measurements were strongly correlated (ρ=0.80), correlated more closely (ρ=0.93) when excluding cases with BSI scores ≥10 (1.8%), and were independently associated with PCa death (p<0.0001 for each) when added to the prediction model. Predictive accuracy of the base model (C-index: 0.768; 95% confidence interval [CI], 0.702-0.837) increased to 0.794 (95% CI, 0.727-0.860) by adding manual BSI scoring, and increased to 0.825 (95% CI, 0.754-0.881) by adding automated BSI scoring to the base model. CONCLUSIONS: Automated BSI scoring, with its 100% reproducibility, reduces turnaround time, eliminates operator-dependent subjectivity, and provides important clinical information comparable to that of manual BSI scoring.

PMID: 22306323 [PubMed - as supplied by publisher]

A case where the principle of “one question, one answer” may work better.

Am Heart J. 2012 Feb;163(2):133-5

Authors: Tada T, Byrne RA, Kastrati A

PMID: 22305827 [PubMed - in process]

Newest-generation drug-eluting and bare-metal stents combined with prasugrel-based antiplatelet therapy in large coronary arteries: The BAsel Stent Kosten Effektivitäts Trial PROspective Validation Examination part II (BASKET-PROVE II) trial design.

Am Heart J. 2012 Feb;163(2):136-141.e1

Authors: Jeger R, Pfisterer M, Alber H, Eberli F, Galatius S, Naber C, Pedrazzini G, Rickli H, Jensen JS, Vuilliomenet A, Gilgen N, Kaiser C

Abstract

BACKGROUND: In the BAsel Stent Kosten Effektivitäts Trial PROspective Validation Examination (BASKET-PROVE), drug-eluting stents (DESs) had similar 2-year rates of death and myocardial infarction but lower rates of target vessel revascularization and major adverse cardiac events compared with bare-metal stents (BMSs). However, comparative clinical effects of newest-generation DES with biodegradable polymers vs second-generation DES or newest-generation BMS with biocompatible coatings, all combined with a prasugrel-based antiplatelet therapy, on 2-year outcomes are not known.

METHODS: In BASKET-PROVE II, 2,400 patients with de novo lesions in native vessels ≥3 mm in diameter are randomized 1:1:1 to receive a conventional DES, a DES with a biodegradable polymer, or a BMS with biocompatible coating. In addition to aspirin, stable patients with BMS will receive prasugrel for 1 month, whereas all others will receive prasugrel for 12 months. The primary end point will be combined cardiac death, nonfatal myocardial infarction, and target vessel revascularization up to 2 years. Secondary end points include stent thrombosis and major bleeding. The primary aim is to test (1) the noninferiority of a biodegradable-polymer DES to a conventional DES and (2) the superiority of both DESs to BMS. A secondary aim is to compare the outcomes with those of BASKET-PROVE regarding the effects of prasugrel-based vs clopidogrel-based antiplatelet therapy.

RESULTS: By the end of 2010, 878 patients (37% of those planned) were enrolled.

CONCLUSIONS: This study will test the comparative long-term safety and efficacy of newest-generation stents on the background of contemporary antiplatelet therapy in a large all-comer population undergoing large native coronary artery stenting.

PMID: 22305828 [PubMed - in process]

Rationale and design of the TAXUS Libertē Post-Approval Study: Examination of patients receiving the TAXUS Liberté stent with concomitant prasugrel therapy in routine interventional cardiology practice.

Am Heart J. 2012 Feb;163(2):142-148.e6

Authors: Garratt KN, Lee DP, Rose EM, Windle KJ, Liao H, Nwachuku CE, Winters KJ, Bowman TS, Dawkins KD

Abstract

BACKGROUND: Observational studies of new coronary stents are necessary to assess performance in a variety of complex patient and lesion types. Furthermore, the optimal dose and duration of thienopyridine treatment is unclear, particularly in patients with complex clinical conditions. The TAXUS Libertē Post-Approval Study is designed to provide 5-year data on the TAXUS Liberté paclitaxel-eluting stent with concomitant prasugrel therapy in routine clinical practice and to contribute data to the DAPT study.

STUDY DESIGN: The TAXUS Libertē Post-Approval Study is a prospective, multicenter, observational study. Enrollment of approximately 4,200 patients receiving ≥1 TAXUS Liberté stents is planned. All patients without a contraindication will be prescribed prasugrel plus aspirin for 1 year. The 12-month primary end point of cardiac death or myocardial infarction in on-label stent patients will be compared with historical TAXUS Express stent data from the TAXUS ATLAS and TAXUS ARRIVE studies. Secondary clinical end points include stent thrombosis, all-cause death, stroke, revascularization, and bleeding in all patients. In addition, this study will be the first to evaluate prasugrel use in a routine practice setting (including 5 and 10 mg daily doses) and will contribute data to the DAPT Study, comparing 12 versus 30 months of dual antiplatelet therapy after drug-eluting stent placement.

SUMMARY: The TAXUS Libertē Post-Approval Study will be the first to provide long-term real-world data on use of the TAXUS Liberté Stent with prasugrel treatment. The study is currently enrolling, and primary end point data are expected in mid 2013.

PMID: 22305829 [PubMed - in process]

Design of the RELAXin in Acute Heart Failure Study.

Am Heart J. 2012 Feb;163(2):149-155.e1

Authors: Ponikowski P, Metra M, Teerlink JR, Unemori E, Felker GM, Voors AA, Filippatos G, Greenberg B, Teichman SL, Severin T, Mueller-Velten G, Cotter G, Davison BA

Abstract

BACKGROUND: Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF.

METHODS: The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 μg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled.

CONCLUSIONS: Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects.

PMID: 22305830 [PubMed - in process]